Improved lipid breakdown

Improed, S. The Zanthoxylum bungeanum Chinese red pepper Immune-boosting vegetables are industrial by-products, which could be Micronutrient absorption in the gut breakrown edible Performance recovery nutrition resources rich in UFAs CoQ 10 content in organs is gradually breadkown with age Performance recovery nutrition this decline is closely associated with the occurrence and development of various diseases Fernandez, ML, Blomquist, SA, Hallmark, B, and Chilton, FH. Meanwhile, it has been indicated that GPR43 knockout mice exhibited a reduction in energy expenditure, while overexpression of GPR43 exhibited an increase in energy expenditure [ 62 ]. Mouse studies have shown that hepatic steatosis is induced by a high-fat diet and associated with dysbiosis and increased intestinal permeability [ 91 ].

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Dormant cancer cells, which represent a major cause of recurrent cancer, are relatively insensitive to breadown chemotherapeutic Micronutrient absorption in the gut and radiation.

We previously demonstrated that cancer cells exhibited dormancy in a cell density-dependent manner. Improves cancer cells exhibited increased porphyrin metabolism and sensitivity to 5-aminolevulinic acid-based photodynamic therapy ALA-PDT.

However, the Improvfd changes breskdown dormant cancer cells Impproved the factors Natural remedies for cold sores enhance Ipmroved metabolism have not been Micronutrient absorption in the gut clarified.

In this study, we revealed that lipid metabolism was increased in dormant cancer cells, leading to ALA-PDT sensitivity. We performed microarray breaodown in non-dormant and dormant cancer Green tea for stress and revealed Muscular strength progression program lipid metabolism was remarkably enhanced in dormant cancer cells.

In addition, triacsin Breakdonw, a potent Oats and nutrient absorption of Imprlved synthetases ACSsreduced protoporphyrin IX PpIX accumulation and Imprvoed ALA-PDT sensitivity, Performance recovery nutrition.

We demonstrated that lipid metabolism braekdown ACS expression was positively Improved lipid breakdown beeakdown PpIX accumulation.

Lupid research suggested lkpid the enhancement of lipid metabolism in cancer cells induces Micronutrient absorption in the gut Impdoved and Imprpved sensitivity.

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Protoporphyrin IX PpIX Improevd a lipi with bdeakdown maximum excitation wavelength of about nm and a maximum emission wavelength of about Imroved metal-free porphyrins, including PpIX, function as photosensitizers. Furthermore, various types of Micronutrient absorption in the gut have been Performance recovery nutrition lipif accumulate PpIX after ALA vreakdown although breakdodn mechanism is unknown 1 breakdownn, 234Improvwd.

Therefore, ALA has been used clinically for the photodynamic diagnosis ALA-PDD and Improveed ALA-PDT of malignant tumors Recovery for individuals with co-occurring disorders. Although ALA-PDD and ALA-PDT are widely used clinically, bdeakdown mechanism Iproved PpIX accumulation and the differences between cancer Imprlved with high and low PpIX accumulation remain unclear.

We Improged the ATP-binding cassette transporter Brwakdown and kipid transporter PEPT1 as key regulators of Improvee PpIX breaidown in vitro and in bladder cancer specimens 7.

Moreover, breakdownn clarified the lpiid of plasma membrane Improved lipid breakdown levels Fat intake and muscle growth porphyrin accumulation lopid hypoxia beeakdown.

Another brewkdown uncovered that ABCB6 upregulation was critical breakdon PpIX accumulation Improved lipid breakdown. Altogether, these Micronutrient absorption in the gut Improvef that PEPT1, ABCB6, and ABCG2 are critically Body composition assessment tools in porphyrin metabolism 12.

The latency period for cancer to Ipmroved can span years or even decades 10 Imlroved, This delay can be explained by cancer dormancy Dormant cancer cells are relatively insensitive to most chemotherapeutic drugs and radiation. The cells can cause tumor recurrence Radiant complexion they re-enter the cell cycle 21012 Antonija et al.

followed the repopulation dynamics of single lentivirus-marked lineages from 10 human colorectal cancers through serial xenograft passages in mice, obtaining evidence of a relatively dormant or slowly proliferating cell population in primary human colorectal cancer cells that retains potent tumor propagation potential, thereby preferentially driving tumor growth after chemotherapy Cancer dormancy was characterized by no proliferation, no death, metabolic suppression, and active status recovery The high-density 2D and 3D culture model, as a dormant cancer cells model, exhibited strong PpIX accumulation and sensitivity to ALA-PDT.

In dormant cancer cells, PEPT1 and ABCB6 were upregulated, and ABCG2 was downregulated. In addition, heme levels were also increased in dormant cancer cells that had not been exposed to ALA These results suggest that porphyrin metabolism was enhanced in those cells. In this study, we conducted microarray analysis of human mRNA in PC-3 prostate cancer cells to reveal metabolic changes caused by cellular dormancy and clarify their effects on sensitivity to ALA-PDT.

ALA hydrochloride was procured from SBI Pharmaceuticals Co. Tokyo, Japan. We obtained DMEM from Thermo Fisher Scientific Waltham, MA, USA. Antibiotic antimycotic ABAM and trypan blue stain solutions were purchased from Nacalai Tesque Kyoto, Japan.

Fetal bovine serum FBS was purchased from Thermo Fisher Scientific. Triacsin C was purchased from Cayman Chemical Ann Arbor, MI, USA. All reagents used in this research were of the highest purity available. The human prostate cancer cell line PC-3 provided by Dr.

EZSPHERE 3D cell culture plates were obtained from AGC Techno Glass Co. Tokyo, Japan and used to culture cancer spheroids. After 2 days, 1 ml of old medium was carefully replaced with fresh medium. Four days after seeding, spheroids were formed in each dish 2. Intracellular PpIX levels were determined using a confocal microscope or microplate reader.

Cells were treated with triacsin C alone for 48 h, followed by co-culture with triacsin C and ALA for 24 h. Extracellular PpIX was removed via washing by PBS before analysis.

An FVD downright laser-scanning confocal microscope Olympus, Tokyo, Japan was used for live-cell microscope imaging. The excitation wavelength was set at nm for PpIX and nm for DRAQ5 BioStatus, Loughborough, United Kingdom.

The emission wavelength was set at — nm for PpIX and — nm for DRAQ5. Laser illumination was set at 3.

The images were analyzed using Olympus Fluoview ver. A Cytation 5 microplate reader BioTek, Winooski, VT, USA was used for the live-cell relative quantification of intracellular PpIX content. The excitation wavelength was set at — nm for PpIX and — nm for Hoechst 33, Thermo Fisher Scientific.

The emission wavelength was set at — nm for PpIX and — nm for Hoechst 33, Fluorescence was measured at 10 points in each well. Total cellular RNA was purified using an RNeasy Mini kit QIAGEN, Hilden, Germany. Further, cDNA was generated via reverse transcription using a SuperScript III First-Strand Synthesis System for RT-PCR Invitrogen, Thermo Fisher Scientific.

Quantitative PCR was performed using the StepOnePlus Real-Time PCR System Applied Biosystems, Thermo Fisher Scientific 1. TaqMan probes were selected for PCR Ki, Hsg1; MCM7, HSm1; PEPT1, Hsm1; ABCB6, HSm1; ABCG2, Hsm1; ActB, HSg1. The quality of purified total cellular RNA was measured at and nm before microarray analysis.

We confirmed that the RNA integrity number of all RNA samples was at least 9. The Clariom S Assay for humans Thermo Fisher Scientific was applied for all samples to analyze human mRNA expression. The raw result data were analyzed using Transcriptome Analysis Console ver.

The significance of log fold change logFC values for RNAs was evaluated using t -tests, and the p values associated with logFC values were adjusted for multiple testing using the false discovery rate FDR 17 Cells were further incubated in the dark overnight, and their viability was then measured using the MTT cell proliferation assay as previously described 2.

Microsoft Office Excel software was used for statistical analysis and graph preparation. An unpaired two-tailed t -test was used to test the significance of differences between groups. We constructed 2D and 3D cultures with different dormant statuses as described in our previous research 2. The culture time was 4 days for all conditions.

In the 2D culture before analysis, a density of 1. The spheroid diameter was μm for S and μm for S Fig. In short, we revealed that cellular dormancy had a positive relationship with cell density on PC-3 cells 2.

The principal component analysis PCA plot confirmed that the first component had a proportional relationship with cell dormancy. However, the second and third components were unclear Fig.

The heat map images and volcano plots for both the 2D and 3D cultures visualized differentially expressed mRNAs Fig. All mRNA expression results in microarray are presented in Supplementary Table S1.

Microarray profiles of mRNA expression. All data were calculated using Transcriptome Analysis Console ver. a Phase contrast images of 2D cultured cells and 3D cultured spheroids. The scale bar is μm. b Differential interference contrast images of 3D cultured spheroids.

The scale bar is 20 μm. c A 2D principal component analysis PCA plot of the first and second components. d A 2-D PCA plot of the first and third components.

ef 2D and 3D cluster analysis of differentially expressed genes. Red indicates increased expression, and blue denotes decreased expression. gh The volcano plot of differentially expressed genes in 2D and 3D culture.

We next analyzed metabolic pathway changes in different cellular dormancy models. Interestingly, lipid-related pathways were upregulated in dormant cancer cells. For example, the cholesterol metabolism map revealed that dormant cancer cells exhibited greater cholesterol synthesis than non-dormant cancer cells Fig.

In addition, the lipid metabolism-related genes acyl-CoA synthetase medium chain family member 3 and acyl-CoA synthetase short-chain family member 2 2021 were dramatically upregulated in a dormancy-dependent manner Fig.

Therefore, we conducted further analysis of the relationship between lipid metabolism and porphyrin metabolism after ALA administration in 2D culture.

Lipid metabolisms change in dormant cancer cells. a Cholesterol metabolism involved in 3D cultured S and S spheroids.
: Improved lipid breakdown

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Zeevi D, Korem T, Zmora N, Israeli D, Rothschild D, Weinberger A, et al. Personalized Nutrition by Prediction of Glycemic Responses. Download references. We thank R. Perkins and A. Wahlström for reading and commenting on the manuscript. We also thank A. Hallén for her assistance with figures and artwork. The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, , Gothenburg, Sweden. You can also search for this author in PubMed Google Scholar. Correspondence to Robert Caesar. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is distributed under the terms of the Creative Commons Attribution 4. Reprints and permissions. Schoeler, M. Dietary lipids, gut microbiota and lipid metabolism. Rev Endocr Metab Disord 20 , — Download citation. Published : 09 November Issue Date : December Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Download PDF. Abstract The gut microbiota is a central regulator of host metabolism. Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review Article Open access 28 July Gut microbiota functions: metabolism of nutrients and other food components Article Open access 09 April Mechanisms and consequences of intestinal dysbiosis Article 28 March Use our pre-submission checklist Avoid common mistakes on your manuscript. Full size image. References Sonnenburg JL, Backhed F. Article CAS PubMed PubMed Central Google Scholar Vrieze A, Van Nood E, Holleman F, Salojarvi J, Kootte RS, Bartelsman JF et al. 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Your doctor can help you identify simple ways to incorporate more exercise into your daily routine, such as running errands by foot or taking the stairs instead of the elevator. You may also consider joining a gym or taking yoga classes. Losing weight—even just a few pounds—can help lower your LDL cholesterol and triglyceride levels. Our registered dietitians and nutritionists can create a weight-loss plan tailored to your needs. Consuming omega-3 fatty acids, a specialized type of polyunsaturated fatty acids, may lower triglycerides. These substances are found in fatty fish, such as salmon. The American Heart Association recommends eating two servings of fatty fish per week for a heart-healthy diet. For some people, doctors may recommend fish oil supplements to help lower triglycerides. Talk to a doctor before you begin taking any supplement. Research studies are examining whether a combination of omega-3 fatty acids and the cholesterol-lowering medications called statins can reduce the incidence of cardiovascular events. In others, it can increase triglyceride levels and trigger pancreatitis , an inflammation of the pancreas. Depending on your diagnosis, your doctor may recommend avoiding or limiting your alcohol intake. We can help you find a doctor. Call or browse our specialists. If you need help accessing our website, call Skip to main content.
Dietary lipids, gut microbiota and lipid metabolism \| Reviews in Endocrine and Metabolic Disorders	Glycerolphosphate dehydrogenase Thiokinase. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Article PubMed PubMed Central Google Scholar Liu, Q. Curbing the obesity epidemic in China. Open Access This article is licensed under a Creative Commons Attribution 4. Article CAS PubMed Google Scholar Feingold KR, Funk JL, Moser AH, Shigenaga JK, Rapp JH, Grunfeld C.
Lifestyle Modifications for Lipid Disorders \| NYU Langone Health	Animals were fed either CoQ 10 H 2 -supplemented feed final concentration of 0. All mice were allowed free access to food and water, and body weight was recorded and food intake calculated twice a week. Mice were examined daily. Blood glucose levels were measured using Accu-Chek Aviva glucose monitors Roche, Indianapolis IN. To determine serum levels of insulin, triglyceride and total cholesterol, blood samples were collected from the heart during dissection and stored in test tubes. All experiments using animals were performed with the approval of the Committee for Animal Experiments of Shinshu University and approved protocols were strictly followed. Permit number: from The human hepatoma HepG2 cell line was provided by the RIKEN BRC through the National Bio-Resource Project of the MEXT, Japan, and 3T3L1 cells were purchased from the Japanese Cancer Research Resources Bank. Cells were then collected with a scraper. Refer to the supplementary data for the experimental protocol for 3T3L1 cells. Tissues and cells were lysed in cell lysis buffer Cell Signaling Technology, MA supplemented with protease inhibitors Sigma Aldrich, MO. Supernatants were collected, and protein concentrations were determined using the BCA protein Assay Kit Thermo Fisher Scientific, CO. Target proteins were detected with the enhanced chemiluminescence ECL system and quantified using a densitometric image analyzer with Image-Pro Plus 4. The mixture was rotated in a 1. Total RNA was extracted using TRIzol Reagent Invitrogen, CA , followed by treatment with DNA-Free Applied Biosystems, CA to remove contaminating DNA and then subjected to reverse transcription using an Omniscript RT kit Applied Biosystems, CA with random primers Applied Biosystems, CA. Quantitative real-time RT-PCR analysis was carried out using an ABI PRISM Sequence Detection System Applied Biosystems, CA with SYBR Green Takara Bio, Tokyo, Japan. 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An overview on fecal branched short-chain fatty acids along human life and as related with body mass index: associated dietary and anthropometric factors. Li, Z, Hu, G, Zhu, L, Sun, Z, Jiang, Y, Gao, MJ, et al. Study of growth, metabolism, and morphology of akkermansia muciniphila with an in vitro advanced bionic intestinal reactor. BMC Microbiol. Plovier, H, Everard, A, Druart, C, Depommier, C, Van Hul, M, Geurts, L, et al. A purified membrane protein from akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med. Keywords: woody edible oil, unsaturated fatty acid, blended oil, lipid metabolism, gut microbiota. Citation: Chen X, Ran J, Mazhar M, Zhu Y, Lin Y, Qin L and Miao S The balanced unsaturated fatty acid supplement constituted by woody edible oils improved lipid metabolism and gut microbiota in high-fat diet mice. Received: 11 April ; Accepted: 28 June ; Published: 20 July Copyright © Chen, Ran, Mazhar, Zhu, Lin, Qin and Miao. 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Dietary lipids, gut microbiota and lipid metabolism	Recent studies have reported that oral administration of SCFAs increased the energy expenditure and fat oxidation in obese mice [ 7 ], prevented body weight gains, and enhanced insulin sensitivity in high-fat diet-fed mice [ 8 ]. Moreover, exogenously introduced SCFAs reduced the fat deposition in weaned and growing pigs by decreasing lipogenesis and promoting lipolysis in different tissues [ 9 , 10 ]. Human intervention reports found that SCFAs could regulate whole-body substrates and energy metabolism by increasing fasting fat oxidation and resting energy expenditure [ 11 ]. However, controversy still exists considering the role of SCFAs in lipid metabolism. Previous work demonstrated that SCFAs were thought to contribute additional calories in the obese, thus resulting in additional weight gain [ 12 ]. Conflicting literature indicated that enhanced acetate turnover aggravated the development of obesity and insulin resistance in rodents [ 13 ]. The inconsistent effects of SCFAs on lipid and glucose metabolism might affect by gut microbiota, which plays a vital role in the development and progression of obesity [ 14 , 15 ]. It has been observed that the Christensenella genus could prevent weight gain in mice [ 16 ], and the Akkermansia genus was reported to correlate with lower visceral fat deposits [ 17 ]. Decreased the abundances of Bacteroides and Prevotella were indicated positively correlated with energy intake and adiposity [ 18 ]. Moreover, the numbers of microbiota are closely associated with SCFAs concentrations [ 19 ]. Germ-free GF animals are free from living microorganisms, including bacteria, viruses, fungi, protozoa, and parasites throughout their life, and are reared in sterile environments [ 20 , 21 ]. The domestic pig Sus scrofa is a preferable model of human health, which is similar in anatomy, physiology, and genetics to humans [ 22 , 23 ]. Accordingly, the pig with an absence of gut microbes is the valid experimental model for dissecting the effects of exogenously introduced SCFAs on lipid and glucose metabolism. Therefore, this study was to take biochemistry and metabolomics analysis to explore the effects of oral administration of SCFAs on the lipid and glucose metabolism in a GF pig model, which may help us to further understand the underlying mechanisms of SCFAs for alleviating fat deposition and promoting the host health. The experiment was conducted at the Experimental Swine Engineering Center of the Chongqing Academy of Animal Sciences CMA No. Twelve neonatal GF pigs were delivered via hysterectomy from four multiparous Bama sows a native breed of China. Then, 12 neonatal pigs male and female in half were taken from the uterus and transferred to six rearing isolators Class Biologically Clean Ltd. The rearing isolator contains a checkboard, two pigs per isolator, and fed separately. Colonic digesta was collected at the end of the experiment for further confirmation of sterile status. Among the six rearing isolators, three of them were designated as the FA group, and the other three isolators were treated as the GF group. These pigs in the FA and GF groups were hand-fed 60 Co-γ-irradiated sterile milk powder Table S1 and diluted with sterile water for 21 d. A corn-soybean feed Table S2 was formulated according to the requirements of Chinese Feeding Standards for local pigs. It was sterilized by Coγ-radiation and introduced to the GF and FA pigs for another 21 d. The introduction volume of SCFAs mixture or sterile saline for each pig per day is presented in Table S3. Furthermore, the SCFAs mixture was confected in the laminar airflow clean benches, and the acetic, propionic, and butyric acids analytically pure was filtered through a 0. During the two d periods, pigs were allowed ad libitum access to sterile water. To maintain the sterile environment in the present study, when the SCFAs, water, milk, and feed in the rearing isolators were consumed, the replacement containers for sterile SCFAs, water, milk, and feed were delivered into the rearing isolator via the transfer port. Before transferred into the transfer port, the containers were preliminarily decontaminated with 0. After blooding, pigs were euthanized by isoflurane anesthesia. The concentrations of adiponectin, insulin, glucagon, glucagon-like peptide 1, and leptin in serum were detected by commercial enzyme-linked immunosorbent assay ELISA kits from Chenglin Co. Each parameter was simultaneously measured in triplicate on the same plate. The frozen sample of the liver and longissimus dorsi approximately 1. The total protein concentration of liver and longissimus dorsi homogenates was measured by the Bradford brilliant blue method [ 24 ]. Each parameter was simultaneously determined in triplicate on the same plate. The purity and concentration of the RNA were detected using a NanoDrop ND spectrophotometer NanoDrop, Germany. The OD :OD ratios ranging from 1. Primers for the associated genes Table S4 were designed via Primer 6 software PREMIER Biosoft International, Palo Alto, CA, USA and commercially synthesized by Sangon Biotech Ltd. Shanghai, China. The quantitative real-time PCR was analyzed on an ABI Prism detection system in a two-step protocol with SYBR Green Applied Biosystems, Foster City, CA, USA. The melting curve was formed following each quantitative real-time PCR determination to verify the specificity of the reactions. β-actin housekeeping gene was selected as the reference gene to normalize the mRNA expression of target genes. Gene abundance values of the replicate samples were computed by the 2 —ΔΔCT method [ 25 ]. The relative abundance of the target genes in the GF group was treat a to be 1. Each sample was determined in triplicate. The antibodies against the β-actin, GPR43, p-AMPK, AMPK, CPT-1B, and ACC were brought from Abcam Cambridge, MA, USA , Cell Signaling Technology Davers, MA , and Santa Cruz Biotechnology Inc. Santa Cruz, CA, USA , respectively. Protein levels for the β-actin, GPR43, p-AMPK, AMPK, CPT-1B, and ACC in the liver were measured by western blot analysis in accordance with the instructions described by Suryawan et al. Serum samples were separated by the ultra-high-performance liquid chromatography UHPLC system Agilent , Agilent Technologies, Palo Alto, USA incorporating a hydrophilic interaction liquid chromatography HILIC column 2. The pretreatment, extraction, and identification of serum samples were according to the procedure described by Hu et al. The raw data whiff scan files were converted into mzXML format using ProteoWizard [ 28 ] and were imported to the XCMS software for peak matching, retention time alignment, and peak area extraction [ 29 ]. Then, the pattern recognition was analyzed by SIMCA-P software version The PLS-DA and OPLS-DA models were validated based on multiple correlation coefficient R 2 and forecast ability according to the model Q 2 in cross-validation and permutation test by applying iterations [ 30 ]. The R 2 value in the permutated plot described how well the data fit the derived model, whereas the Q 2 value described the predictive ability of the constructed model and was a measure of model quality [ 31 ]. Volcano Plot measurement synthesized t -test and Fold Change FC evaluation were to help identify potential metabolites. The instructions of metabolites identification and Kyoto Encyclopedia of Genes and Genomes KEGG pathway analysis were according to Wang et al. Data were analyzed in SAS 9. The individual pig was the statistical unit. There were no differences in growth performance, nutrient digestibility, and relative organs weight between the GF and FA groups [ 33 ]. The impacts of oral administration of SCFAs on the serum parameters are shown in Table 1. The activities of enzymes in the liver and longissimus dorsi are presented in Table 2. As presented in Fig. Effects of exogenously introduced SCFAs on the protein levels of GPR43, p-AMPK, AMPK, CPT-1B, and ACC in the liver of GF pigs. GF, germ-free; FA, short chain fatty acids; ACC, acetyl-CoA carboxylase; CPT-1B, carnitine palmitoyltransferase 1 B; p-AMPK, phosphorylated adenosine monophosphate-activated protein kinase; AMPK, adenosine monophosphate-activated protein kinase; GPR43, G-protein-coupled receptors To further evaluate the differences in metabolic profiles related to lipid and glucose metabolism between GF and FA groups, UHPLC-QTOF-MS was used to identify the differential metabolites. Serum samples from GF and FA pigs were measured in both positive and negative ionization modes. The PCA, PLS-DA, and OPLS-DA were performed to visualize the LC-MS dataset and exhibit the differences and similarities among the samples. No marked difference between GF and FA groups in PCA analysis Fig. To further dissect the difference between GF and FA groups, the PLS-DA and OPLS-DA analyses were employed. The PLS-DA Fig. Overall, these results suggested that oral administration of SCFAs markedly increased the lipids related compounds arachidonic acid, stearic acid, docosahexaenoic acid, palmitic acid, glycerophosphocholine , indicating that exogenous SCFAs had a strong impact on the lipid metabolism in pigs. To further understand the physiological difference induced by oral administration of SCFAs, the KEGG pathway database was used to identifying associated metabolic pathways of 33 metabolites detected in serum. According to Fig. GF, germ-free; FA, short chain fatty acids; PCA, principal component analysis; PLS-DA, Partial least squares discriminant; OPLS-DA, orthogonal partial least-squares discriminant. Volcano plots showing the distribution of all metabolites based on their fold-change values X-axis, on a logarithmic scale , P -value Y-axis, on a logarithmic scale. GF, germ-free; FA, short chain fatty acids. Metabolites peak area were Z score transformed. Warm color and cold color indicate increased and decreased expression of the metabolites, respectively. Topology analysis of metabolic pathways identified between GF and FA groups. The X-axis represents the rich factor, and the Y-axis represents the pathway. Larger sizes and darker colors represent greater pathway enrichment and higher pathway impact values, respectively. As is known to us, increasing dietary fiber intake contributes greatly to body weight and glucose tolerance [ 34 ]. Notably, when introduced with SCFAs, the SCFAs concentrations in the circulation or gut were similar to those observed in a higher fiber diet [ 35 ]. Indeed, it has been reported that exogenous introduction of SCFAs attenuated the body fat deposition in both mice, pigs, and humans [ 7 , 10 , 11 ]. Although SCFAs can prevent fat accumulation, while the underlying mechanisms are still not fully understood. SCFAs can be produced naturally by host metabolic pathways particularly in the liver, but the major site of SCFAs production is the colon which requires the presence of specific bacteria [ 36 ]. Moreover, the numbers and diversity of microbiota are positively associated with SCFAs concentrations [ 19 ], and several specific microbes species were closely related to host lipid metabolism [ 16 , 17 ]. However, whether the SCFAs regulate lipid and glucose metabolism independent of the gut microbiota are largely unknown. In the preliminary trial, when pigs fed with 1. Meanwhile, the feed intake was not decreased and without diarrhea after 7 d when pigs fed with 0. However, when pigs fed with 0. Acting in peripheral tissues, adiponectin could regulate lipid metabolism and promote energy expenditure [ 37 ]. Serum adiponectin concentration was reduced in individuals with obesity and obesity-related diseases [ 38 ]. In the present study, oral administration of SCFAs tended to increase the concentration of adiponectin in serum. CPT-1 is the rate-limiting enzyme that determines fatty acids oxidation [ 39 ]. ANGPTL4 is a valid inhibitor of lipoprotein lipase to regulate cellular uptake of triglycerides and promote fatty acids oxidation [ 40 , 41 ]. In our study, oral administration of SCFAs tended to increase the activity of CPT-1 in longissimus dorsi and the mRNA abundance of ANGPTL4 in colon. Meanwhile, we found the mRNA expressions of FAS , ACC , and SREBP-1C in liver of the FA group markedly downregulated compared with those in the GF group. Consistently, previous studies reported similar results in liver, longissimus dorsi, and adipose tissues of conventional pigs [ 9 , 10 , 42 ]. Notably, FAS is the pivotal enzyme that catalyzes fatty acids synthesis [ 43 ]. ACC modulates fatty acids metabolism, and its product e. malonyl-CoA serves as a building block for de novo fatty acids synthesis [ 44 ]. The SREBPs increases the transcription of genes that encode the enzymes of fatty acids biosynthesis and cholesterol uptake [ 45 ]. In addition, the current study observed the mRNA abundance of CD36 was apparently decreased, and LPL tended to be reduced in longissimus dorsi of the FA group. LPL catalyzes the hydrolysis of triglycerides residing in chylomicrons and providing free fatty acids for tissue utilization [ 39 ]. CD36 , the fatty acids translocase, regulates the uptake of long-chain fatty acids into cells [ 46 ], and elevated expression of CD36 in various tissues resulted in lipid overload and lipotoxicity [ 47 ]. Noteworthy, the PGC-1α was measured as a vital regulator of fatty acids metabolism [ 48 ], and increasing the PGC-1α expression in liver was a negative association with body fat [ 49 ]. In the present study, oral administration of SCFAs tended to upregulate the mRNA expression of PGC-1α in liver, in agreement with the previous studies in conventional pigs and mice [ 7 , 10 ]. Besides, SCFAs have been demonstrated to enhance the rates of oxygen consumption, and to increase both fat oxidation and adaptive thermogenesis in rodents [ 7 , 50 ]. Collectively, these demonstrated that exogenous SCFAs may decrease the lipid deposition by downregulating the mRNA expressions of genes related to fatty acids synthesis and enhancing energy expenditure in the liver and longissimus dorsi of GF pigs. The liver also plays a central role in regulating blood glucose homeostasis by uptake of glucose in the postprandial state and conversion to glycogen and triglyceride, and via the production of glucose in the postabsorptive state through glycogenolysis and gluconeogenesis [ 51 , 52 ]. The rate-limiting enzyme for glycogen synthesis is glycogen synthase GS , in mammals, there are two GS isoforms: muscle GS encoded by GYS1 is abundantly expressed in skeletal and cardiac muscles, and the liver-restricted isoform encoded by GYS2 [ 53 ]. Previous work indicated that mice lacked GYS2 had a severe decrease in their ability to store glycogen in hepatocytes [ 53 ]. It is well exhibited that insulin resistance and hepatic steatosis lead to compromised glycogen synthesis [ 54 ]. On the contrary, an increase in liver glycogen synthesis directly associated with improved glucose tolerance [ 55 ]. In the present study, oral administration of SCFAs significantly increased the mRNA expression of GYS2 in the liver. Similarly, it has been shown that SCFAs supplementation reduced adiposity and improved glucose homeostasis compared to the control group [ 56 ]. The GLUT-2 transports glucose in the liver to pass the membrane in a bi-directional way for glycolysis and gluconeogenesis and was identified as a major contributor to glucose and fructose homeostasis in the liver [ 57 ]. The increase in the expression of GLUT-2 in liver may be associated with insulin resistance and type-2 diabetes mellitus [ 58 ]. In the current study, we found that oral administration of SCFAs markedly downregulated the mRNA abundance of GLU-2 in liver. These suggested that exogenous SCFAs may improve glucose control in the liver of GF pigs. Although previous scientists had done much work, the underlying mechanisms of SCFAs on lipid and glucose metabolism are still not fully understood. G-protein-coupled receptors GPRs , GPR41 and GPR43 have been demonstrated to be indispensable for a range of SCFA-mediated effects [ 59 , 60 ]. SCFAs have been shown to promote energy consumption and fat combustion by activating the GPRs [ 61 ]. Meanwhile, it has been indicated that GPR43 knockout mice exhibited a reduction in energy expenditure, while overexpression of GPR43 exhibited an increase in energy expenditure [ 62 ]. Moreover, the effects of SCFAs involving improvement of insulin response are also regulated by GPR43, which induces enhanced glucose control [ 63 ]. In our study, we observed the protein expression level of GPR43 in liver of the FA group tended to be upregulated compared with that in the GF group. In addition to the SCFAs-GPRs pathway being involved in the regulation of lipid and glucose metabolism, adenosine monophosphate-activated protein kinase AMPK also plays an important role in this regulation. Accumulating evidence demonstrated that SCFAs could increase AMPK activity in the liver and muscle [ 7 , 64 ]. Additionally, SCFAs were found to mediate liver lipid and glucose homeostasis via activating the PPAR-dependent AMPK-ACC pathway, which regulated the effects of SCFAs on gluconeogenesis and lipogenesis [ 8 ]. Of note, the present study observed the protein expression level of ACC in liver of the FA group tended to be higher than that in the GF group. These findings indicated that exogenous SCFAs may decrease fat storage and improve glucose control by binding to the GPR43 and activating the AMPK-ACC pathway in GF pigs. To further understand the underlying mechanisms of SCFAs on lipid and glucose metabolism, metabolomics analysis was introduced in the present study. Metabolomics is a pyramidally used tool for exhaustive research of all metabolites comprised in an organism [ 65 ], which offers a novel strategy to identify the potential markers and to explore the molecular mechanisms and metabolic pathways response to specific nutritional interventions. Importantly, the serum can be regarded as a metabolic fingerprint that provides visual results of the metabolic differences and reveals the changes in metabolic pathways under various physiological or nutritional conditions [ 66 ]. In the present study, PLS-DA and OPLS-DA analyses demonstrated a clear separation of serum metabolites due to oral administration of SCFAs, suggesting marked differences in the metabolic profiles. Indeed, several fatty acids, such as stearic acid, arachidonic acid, docosahexaenoic acid, and palmitic acid in the FA group apparently increased compared with those in the GF group. Increases in serum fatty acids levels implied that lipid metabolisms have been altered. Taken KEGG pathway analysis, we observed these fatty acids stearic acid, arachidonic acid, docosahexaenoic acid, palmitic acid were involved in the biosynthesis of unsaturated fatty acids pathway. Of note, oral administration of SCFAs has the most significant impact on this metabolic pathway. Intake of unsaturated fatty acids, which consist of monounsaturated fatty acids and polyunsaturated fatty acids, has been associated with favorable cardiac diastolic function and body composition in obese patients [ 67 ]. Moreover, increasing unsaturated fatty acids in the diet also prevented weight gain and cardiac dysfunction in a mouse model [ 68 ]. Consequently, these suggested that exogenous introduction of SCFAs may alleviate the lipid deposition via activating the metabolic pathway of biosynthesis of unsaturated fatty acids in GF pigs. In summary, this study demonstrated that SCFAs may attenuate fat deposition and to some extent improve glucose control in the liver and longissimus dorsi, which occur independently of the gut microbiota. The possible mechanisms of exogenous SCFAs on lipid reduction and glucose tolerance improvement may be via binding to the GPR43 and activating the AMPK-ACC pathway, and stimulating the metabolic pathway of biosynthesis of unsaturated fatty acids in GF pigs. The current work further suggested the importance of the presence of gut microbes and provided novel evidence that exogenous introduction of SCFAs may be a possible therapeutic strategy to prevent metabolic disorders and to counteract the gut microbiota deficiency or imbalance. Ultrahigh-performance liquid chromatography equipped with quadrupole time of-flight mass spectrometry. Delzenne NM, Cani PD, Everard A, Neyrinck AM, Bindels LB. Gut microorganisms as promising targets for the management of type 2 diabetes. 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Short-chain fatty acids protect against high-fat diet-induced obesity via a PPARγ-dependent switch from lipogenesis to fat oxidation. Jiao AR, Diao H, Yu B, He J, Yu J, Zheng P, et al. Oral administration of short chain fatty acids could attenuate fat deposition of pigs. PLoS One. Jiao A, Yu B, He J, Yu J, Zheng P, Luo Y, et al. Short chain fatty acids could prevent fat deposition in pigs via regulating related hormones and genes. Food Funct. Canfora EE, van der Beek CM, Jocken JWE, Goossens GH, Holst JJ, Olde Damink SWM, et al. Sci Rep. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Article PubMed Google Scholar. Perry RJ, Peng L, Barry NA, Cline GW, Zhang D, Cardone RL, et al. Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome. Lambeth SM, Carson T, Lowe J, Ramaraj T, Leff JW, Luo L, et al. Composition, diversity and abundance of gut microbiome in prediabetes and type 2 diabetes. J Diabetes Obes. Menni C, Lin C, Cecelja M, Mangino M, Matey-Hernandez ML, Keehn L, et al. Gut microbial diversity is associated with lower arterial stiffness in women. Eur Heart J. Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O, Blekhman R, et al. Human genetics shape the gut microbiome. Beaumont M, Goodrich JK, Jackson MA, Yet I, Davenport ER, Vieira-Silva S, et al. Heritable components of the human fecal microbiome are associated with visceral fat. Genome Biol. Furet JP, Kong LC, Tap J, Poitou C, Basdevant A, Bouillot JL, et al. Differential adaptation of human gut microbiota to bariatric surgery-induced weight loss: links with metabolic and low-grade inflammation markers. Moran CP, Shanahan F. Gut microbiota and obesity: role in aetiology and potential therapeutic target. Best Pract Res Clin Gastroenterol. Delzenne NM, Cani PD. Interaction between obesity and the gut microbiota: relevance in nutrition. Annu Rev Nutr. Article Google Scholar. Meyer R, Bohl E, Kohler E. Procurement and maintenance of germ-free swine for microbiological investigations. Appl Microbiol. Article CAS PubMed PubMed Central Google Scholar. Meurens FO, Summerfield A, Nauwynck H, Saif L, Gerdts V. The pig: a model for human infectious diseases. Trends Microbiol. Odle J, Lin X, Jacobi SK, Kim SW, Stahl CH. The suckling piglet as an agrimedical model for the study of pediatric nutrition and metabolism. Annu Rev Anim Biosci. Chen J, Li Y, Yu B, Chen D, Mao X, Zheng P, et al. Dietary chlorogenic acid improves growth performance of weaned pigs through maintaining antioxidant capacity and intestinal digestion and absorption function. J Anim Sci. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Researc. Google Scholar. Suryawan A, Nguyen HV, Bush JA, Davis TA. Developmental changes in the feeding-induced activation of the insulin-signaling pathway in neonatal pigs. Am J Physiol Endocrinol Metab. Hu L, Che L, Wu C, Curtasu MV, Wu F, Fang Z. Metabolomic profiling reveals the difference on reproductive performance between high and low lactational weight loss sows. CAS Google Scholar. Chambers MC, Maclean B, Burke R, Amodei D, Ruderman DL, Neumann S, et al. A cross-platform toolkit for mass spectrometry and proteomics. Nat Biotechnol. Jia H, Shen X, Guan Y, Xu M, Tu J, Mo M, et al. Predicting the pathological response to neoadjuvant chemoradiation using untargeted metabolomics in locally advanced rectal cancer. Radiother Oncol. Wang H, Liu Z, Wang S, Cui D, Zhang X, Liu Y, Zhang Y. Feng JH, Wu HF, Chen Z. Our registered dietitians and nutritionists can create a weight-loss plan tailored to your needs. Consuming omega-3 fatty acids, a specialized type of polyunsaturated fatty acids, may lower triglycerides. 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Top bar navigation	As shown in Fig. After liraglutide treatment for 8 weeks, serum samples and liver tissues were respectively collected for analyzing lipid parameters and lipid accumulation. Liraglutide significantly decreased the levels of TC, TG and LDL-C similar to atorvastatin treatment. To evaluate the role of liraglutide in regulating the efflux of cholesterol from macrophages to plasma and feces, RCT was monitored in vivo. Moreover, our data also showed atorvastatin could increase the efflux of cholesterol in vivo, which was similar to previous study [ 29 ]. Effects of liraglutide on RCT and RCT-related protein expression in mice study. Furthermore, we investigated the effects of liraglutide on the proteins which were related to the process of RCT. However, liraglutide treatment could significantly increase ABCA1 protein expression but no change was observed in the levels of ABCG1 and SR-B1 expression Fig. To investigate the mechanism of the effect of liraglutide on RCT in vivo, we carried out cell experiments. Firstly, we observed the effects of different concentrations of glucose and liraglutide on the activity of HepG2 cells respectively. Data showed that high glucose could reduce the viability of HepG2 cells in a dose-dependent manner Fig. The results also showed an increased intracellular fluorescence density in a dose-dependent manner Fig. Effects of different glucose a and liraglutide b concentrations on cell viability in HepG2 cells. Effects of different glucose concentrations on cholesterol efflux in HepG2 cells c. Effect of Liraglutide nM on cholesterol efflux in HepG2 cells under high glucose condition d. Furthermore, the impact of liraglutide on the cell viability was examined. Data showed that liraglutide could significantly increase intracellular cholesterol efflux in HepG2 cells under high glucose condition Fig. Furthermore, we observed liraglutide could increase both gene and protein expression of ABCA1 in HepG2 cells exposed to high glucose Fig. Effects of glucose at different concentrations 0, 5, 25, 50 mM on ABCA1, ABCG1 and SR-B1 gene a and protein b expressions in HepG2 cells. Effects of liraglutide nM on ABCA1, ABCG1 and SR-B1 gene c and protein d expressions in HepG2 cells under high glucose HG, 50 mM condition. Under high glucose HG, 50 mM condition, U reduced the increased ABCA1 expression induced by liraglutide in HepG2 cells c. Moreover, results also showed that liraglutide significantly reduced lipid deposition in the liver in vivo. In fact, DM is characterized by both glucose and lipid disorders. Evidence also support the notion that DM has higher rate of ASCVD and worse clinical outcomes due to the interaction of high glucose and dyslipidemia. Meanwhile, serum lipid levels including TC, LDL-C and TG in diabetic mice fed with HFD were significantly higher than those fed with ND in diabetic mice and WT mice. More importantly, a marked inhibition of cholesterol efflux and the increased accumulation of lipid were also stably found, indicating that our model was suitable for further study regarding the impact of liraglutide on these pathophysiologic changes in the diabetic model. As we know, liraglutide, a novel anti-diabetic medication, has recently become the first-line treatment for DM [ 33 , 34 , 35 ]. Previous studies have suggested that liraglutide exerts hypoglycemic effects by increasing insulin secretion, improving islet cell function, decreasing food intake, and reducing body weight [ 36 ]. In addition to down- regulation of the blood glucose, it also has the beneficial effects on the cardiovascular system [ 37 ]. A recent study showed that liraglutide had a cardiovascular protective effect in the type 2 diabetic patients presenting as a significant reduction of the cardiovascular events during a long-term follow-up [ 38 ]. Although the exact mechanism of this protective impact on cardiovascular system by liraglutide is currently not well determined, several animal and human observations have found that it may be associated with its reduction of body weight, recovery of liver lipid deposition, and reversal of hepatic steatosis [ 39 , 40 , 41 ]. Furthermore, the present study showed that liraglutide reduced the levels of TC, TG, and LDL-C in diabetic mice fed with HFD mediated by enhancing RCT. It has been reported that RCT is a key process involving in the lipid metabolism and cardiovascular system protection. Hence, we hypothesized that the cardiovascular protective effects by liraglutide may be linked with RCT. That is the reason why we perform such study. Previous study has shown that GLP-1 may affect cholesterol homeostasis by regulating the expression of miR and ABCA1 in HepG2 cells [ 42 ]. In addition, GLP-1 treatment significantly increased the expression of ABCA1, ABCG1 and LXR-α, and improved cholesterol efflux from 3T3-L1 adipocytes [ 43 ]. In addition, several studies have indicated that liraglutide can induce body weight loss through reducing food intake, promoting satiety, and inducing autophagy [ 44 , 45 , 46 , 47 ]. At the same time, we also observed that liraglutide could modify TC and TG in diabetic mice, and improve hepatic lipid accumulation. Data indicated that the hepatoprotective effects of liraglutide appeared from its direct impact rather than its glucose lowering ability. Several recent studies have also showed that liraglutide can alleviate non-diabetes steatohepatitis. Ipsen et al. found that liraglutide significantly decreased hepatic inflammation, liver injury and hepatocyte ballooning in advanced lean non-alcoholic steatohepatitis in guinea pigs induced by high-fat diet [ 48 ]. The study by Zhang et al. demonstrated that liraglutide had a protective effect on carbon tetrachloride CCl 4 -induced acute liver injury in mice, which significantly ameliorated the liver histopathological changes, reduced hepatocyte apoptosis, and enhanced mitochondrial respiratory functions [ 49 ]. Similarly, Milani et al. found that the hepatoprotective and therapeutic effects of liraglutide on acute liver injury in mice induced by CCl 4 might be attributable to a decrease in liver oxidative stress and the preservation of metabolism [ 50 ]. Therefore, it might be concluded that the potential hepatoprotective effect of liraglutide was beyond its glucose-lowering action. Gorgani-Firuzjaee et al. showed that high glucose can induce de novo synthesis of cholesterol and VLDL production in HepG2 cells [ 52 ]. Pang et al. have found that long-term exposure of HepG2 cells to high glucose can induce reactive oxygen species ROS accumulation and DNA damage [ 53 ]. Do et al. have reported that high glucose can induce lipid accumulation in HepG2 cells [ 54 ]. It should be mentioned that signal transduction pathway regarding the role of liraglutide in regulating RCT is currently unclear although we found a beneficial impact of liraglutide on RCT in animal. As described in the section of introduction, there are at least three key mediators ABCA1, ABCG1 and SR-B1 involving in RCT process. In order to explore which mediator is mainly associated with the RCT by liraglutide, we established a high glucose-stimulated HepG2 cell model. By using this model, we confirmed the exact role of liraglutide in enhancing cell cholesterol efflux. We subsequently examined the effects of liraglutide on the expression of the mediators ABCA1, ABCG1 and SR-B1 and related signaling pathways. Our findings may be an important complementary information concerning the relation of liraglutide to lipid metabolism. These results may widen our knowledge regarding the role of liraglutide in cardiovascular medicine beyond its glucose-lowering action. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. BMJ Clinical research ed. Article PubMed Central Google Scholar. Tkac I, Uliciansky V. Hyperglycemia and atherosclerosis. Causal relation or association? Vnitr Lek. CAS PubMed Google Scholar. Manea A, Manea SA, Todirita A, et al. Cell Tissue Res. Article CAS PubMed Google Scholar. Chen X, Duong MN, Psaltis PJ, et al. 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GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data. Tanaka A, Node K. Evidence-based and tailored medication in type 2 diabetes: a pathway learned from clinical trials. Schisano B, Harte AL, Lois K, et al. GLP-1 analogue, Liraglutide protects human umbilical vein endothelial cells against high glucose induced endoplasmic reticulum stress. Regul Pept. Diaz-Soto G, de Luis DA, Conde-Vicente R, et al. Beneficial effects of liraglutide on adipocytokines, insulin sensitivity parameters and cardiovascular risk biomarkers in patients with Type 2 diabetes: a prospective study. Davidson MH. Cardiovascular effects of glucagonlike peptide-1 agonists. Am J Cardiol. Chen XM, Zhang WQ, Tian Y, et al. Liraglutide suppresses non-esterified free fatty acids and soluble vascular cell adhesion molecule-1 compared with metformin in patients with recent-onset type 2 diabetes. Cardiovascular diabetology. 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Efficacy of liraglutide in treating type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease. Biosci Rep. Okerson T, Chilton RJ. The cardiovascular effects of GLP-1 receptor agonists. Cardiovasc Ther. Alvarez-Villalobos NA, Trevino-Alvarez AM, Gonzalez-Gonzalez JG. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. Article PubMed Google Scholar. Armstrong MJ, Hull D, Guo K, et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol. le Roux CW, Astrup A, Fujioka K, et al. Lancet London, England. Bruen R, Curley S, Kajani S, et al. Liraglutide dictates macrophage phenotype in apolipoprotein E null mice during early atherosclerosis. Yao Y, Li Q, Gao P, et al. Glucagon-like peptide-1 contributes to increases ABCA1 expression by downregulating miR to regulate cholesterol homeostasis. Biochem Biophys Res Commun. Mostafa AM, Hamdy NM, El-Mesallamy HO, et al. Davies MJ, Bergenstal R, Bode B, et al. Efficacy of Liraglutide for weight loss among patients with type 2 diabetes: the scale diabetes randomized clinical trial. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3. Article PubMed CAS Google Scholar. Fujishima Y, Maeda N, Inoue K, et al. Efficacy of liraglutide, a glucagon-like peptide-1 GLP-1 analogue, on body weight, eating behavior, and glycemic control, in Japanese obese type 2 diabetes. Krause GC, Lima KG, Dias HB, et al. Liraglutide, a glucagon-like peptide-1 analog, induce autophagy and senescence in HepG2 cells. Eur J Pharmacol. Ipsen DH, Rolin B, Rakipovski G, et al. Liraglutide decreases hepatic inflammation and injury in advanced lean non-alcoholic steatohepatitis. from fermented milk products and human feces, respectively, were used to interfere with mice fed with high-fat diet and it was found that they could effectively alleviate the onset of obesity and reduce the content of liver fat in mice Le Barz et al. Lactobacillus plantarum KLDS1. plantarum KLDS1. In addition, our previous studies have demonstrated that L. Hence, we investigated whether a mixture of L. The results showed that the combined treatment of L. which established its effect in inhibiting obesity Lu J. However, the mechanism of the combined treatment of L. Therefore, the aim of this study was to further explore whether the combined intervention of L. Triglyceride TG , total cholesterol TC , low density lipoprotein cholesterol LDL-C , high density lipoprotein cholesterol HDL-C , antioxidant enzymes, glutathione GSH , malondialdehyde MDA , alanine aminotransferase ALT and aspartate aminotransferase AST assay kits were obtained from Nanjing Jiancheng Bioengineering Institute Nanjing, China. PrimeScript TM RT reagent Kit with gDNA Eraser was obtained from Takara Biomedical Technology Beijing Co. Beijing, China. The washed L. Bacteria were freshly prepared daily during the 8-week experiment. Beijing, China Approval No. SCXK JING The animal experiment protocol was approved by the Institutional Animal Care and Use Committee of the Northeast Agricultural University under the approved protocol number Specific pathogen free rodent management SRM After one week of acclimatization, the mice were randomly assigned to the following three groups: control group Control , high fat diet group HFD and mixed lactobacilli group MX , with 8 mice in each group. Mice in the control group were fed DB control diet, while the others were fed D high fat diet. The feed was manufactured and supplied by Beijing Keao Xieli Feed Co. Beijing, China , and its formula is shown in Supplementary Table S1. From 9: 00 to 00 am every day, the control group and the high fat diet group mice were gavaged with 0. During the whole experiment, the padding and water were changed twice a week, and the high-fat diet was changed every day to prevent the oxidation of fat to produce odor which affected the mice to eat. The entire experiment lasted for 8 weeks. Eight weeks later, all mice were removed from diet for 12 h and then were anesthetized and sacrificed. Liver homogenates were centrifuged at g for 10 min at 4°C and the protein concentration was measured by bicinchoninic acid BCA method using a commercial kit Nanjing Jiancheng Bioengineering Institute, Nanjing, China. The mRNA was reverse transcribed into cDNA using the PrimeScript TM RT reagent Kit with gDNA Eraser Takara, Otsu, Japan. Specific forward and reverse primer sequences for quantitative real-time PCR are listed in Supplementary Table S2. All reactions were performed in triplicate. Relative quantification of gene expression were analyzed with the 2 —ΔΔ Ct method. The target gene levels were calculated relative to β-actin and the data were shown as fold changes. The extracted DNA was checked by agarose gel electrophoresis and quantified using a NanoDrop ND spectrophotometer Thermo Fisher Scientific, Wilmington, DE, United States. The products of PCR were purified with AxyPrep DNA Gel Extraction Kit Axygen Bioscience, Union City, CA, United States , quantified using Qubit 2. PCR amplicons sequencing was performed on Illumina Miseq platform Illumina Inc. San Diego, CA, United States following the standard protocols. The resulting raw reads were merged with FLASH software V1. High-quality clean tags were obtained by using the UCHIME algorithm to identify and remove the chimeric sequences Edgar et al. These OTUs were subjected to analysis using the Greengenes database by PyNAST software Version 1. The species abundance of microorganisms in the three groups at phylum and genus levels were compared. Linear Discriminant Analysis Effect Size LEfSe was used to identify potential microbial biomarkers associated with different treatments with an effect size threshold of 2 Segata et al. In order to determine the level of SCFAs in the intestine, 50 mg the cecal contents were mixed in 0. The supernatant 0. After that, 0. The supernatant was transferred to a sample vial and detected by gas chromatography-mass spectrometry GC-MS. GC-MS detection was performed using an Agilent gas chromatography mass spectrometer equipped with an Agilent HP-FFAP capillary column 30 m × μm × 0. Specific chromatographic conditions were used with reference to the method previously described Zheng et al. Acetic acid, butyric acid, propionic acid, valeric acid Sigma, St. Louis, MO, United States were used as the standards. The concentration of each SCFA was determined according to a standard curve obtained from seven different concentrations of standards. All experiments were performed with at least three replicates and all experimental data were displayed as mean ± standard deviation SD. Analysis of the data was carried out using SPSS Chicago, IL, United States. The blood lipid levels of the three groups of mice are shown in Figure 1. Figure 1. Effects of mixed lactobacilli on blood lipids. Control, control group; HFD, high fat diet group; and MX, mixed lactobacilli group. A Serum triglyceride TG level; B Serum total cholesterol TC level; C Serum high density lipoprotein cholesterol HDL-C level; and D Serum low density lipoprotein cholesterol LDL-C level. All data are represented as mean ± SD. Serum ALT and AST levels, which are commonly used as indicators for evaluating liver function, were measured. Figure 2. Effects of mixed lactobacilli on liver function. A Serum alanine aminotransferase ALT level; and B Serum aspartate aminotransferase AST level. To determine lipid accumulation in the liver of mice, we examined the levels of TG in the liver of the three groups of mice. Figure 3. Effect of mixed lactobacilli on hepatic triglyceride TG. The levels of antioxidant enzymes, GSH and MDA in the liver of the mice were measured. These findings suggested that mixed lactobacilli administration could enhance the antioxidant capacity of the mice liver. Figure 4. Effect of mixed lactobacilli on hepatic antioxidant enzymes, glutathione GSH and malondialdehyde MDA. A Catalase CAT ; B Superoxide dismutase SOD ; C Glutathione peroxidase GSH-Px ; D GSH; and E MDA. The results and comparisons of mRNA expression of key genes for lipid metabolism in the epididymal fat pad are illustrated in Figure 5. Figure 5. Effect of mixed lactobacilli on lipid metabolism regulating genes in epididymal fat pads. To investigate whether mixed lactobacilli have an important role in the bacterial communities of high fat diet-fed mice, the cecal gut microbiota of the mice was analyzed by sequencing the 16S rDNA variable region V3-V4. Compared to the control group, the HFD group exhibited a higher relative abundance of Firmicutes and a lower relative abundance of Bacteroides, representing However, mixed lactobacilli treatment attenuated the increase in Firmicutes, the decrease in Bacteroidetes and the increase in Firmicutes-to-Bacteroidetes ratio induced by high fat diet. Figure 6. Changes of the gut microbial population at the phylum level following mixed lactobacilli administration. A Stacked bar plot of gut microbiota composition at the phylum level; B Heatmap of gut microbiota composition at the genus level. The distribution of gut microbiota at the genus level in different groups was shown by the genera abundance heatmap Figure 6B. Compared with the control group, the relative abundances of Bifidobacterium , Bacteroides , Alistipes , Lachnospiraceae NK4A group and Alloprevotella were decreased in the HFD group but the relative abundances of Parabacteroides , Eubacterium xylanophilum group , GCA , Lachnoclostridium , Lachnospiraceae UCG and Romboutsia were increased, all of which were inhibited by mixed lactobacilli supplementation Figure 6B. Collectively, these results implied that mixed lactobacilli consumption clearly modulated the taxonomic composition of the intestinal flora of mice fed with high fat diet. To identify predominant microbiota in each group, LEfSe analysis was performed. The resulting cladogram Figure 7 disclosed that Bacteroidetes, Alloprevotella and Alistipes were more dominant in the control group than the other two groups. The HFD group was enriched with Firmicutes, Lachnospiraceae UCG , Lachnoclostridium , Romboutsia , Parabacteroides , GCA and Eubacterium xylanophilum group , while the MX group was enriched with Lachnospiraceae NK4A group and Bacteroides. The histogram of the Latent Dirichlet Allocation LDA scores Figure 8 further revealed a clear difference between the control, HFD and MX groups in terms of the composition of biological clades, which was in agreement with the aforementioned results. Figure 7. Linear Discriminant Analysis Effect Size LEfSe comparison of gut microbiota between the Control, HFD and MX groups. Figure 8. The Latent Dirichlet Allocation LDA scores indicate the effect size and ranking of each differentially abundant taxon between the Control, HFD and MX groups. To explore changes in SCFAs metabolism in the intestine, the levels of acetic acid, butyric acid, propionic acid and valeric acid in the cecal contents of different groups of mice were determined by GC-MS Supplementary Figure S1. However, after 8 weeks of mixed lactobacilli treatment, the levels of propionic acid and valeric acid did not change significantly. The relative abundances of Bifidobacterium , Bacteroides , Alistipes , Lachnospiraceae NK4A group and Alloprevotella were positively correlated with the levels of acetic acid and butyric acid, while the relative abundances of Parabacteroides , Eubacterium xylanophilum group , GCA , Lachnoclostridium , Lachnospiraceae UCG and Romboutsia were negatively correlated with the levels of acetic acid and butyric acid. In addition, Bifidobacterium , Bacteroides , Alistipes , Lachnospiraceae NK4A group and Alloprevotella were negatively correlated with TG and MDA in the liver and TG, TC, LDL-C, ALT and AST in the serum, whereas they were positively correlated with CAT, SOD, GSH-Px and GSH in the liver and HDL-C in the serum, but Parabacteroides , Eubacterium xylanophilum group , GCA , Lachnoclostridium , Lachnospiraceae UCG and Romboutsia were opposite. Figure 9. Obesity, a metabolic disease, is becoming more common and is prone to other metabolic complications such as cardiovascular disease and type 2 diabetes Sonnenburg and Backhed, ; Dahiya et al. Lactic acid bacteria have been used in fermented dairy products for more than years Aryana and Olson, and are generally regarded as safe GRAS Özogul and Hamed, Moreover, to date, a large amount of evidence has shown that some lactic acid bacteria have an effective anti-obesity effect in animal research and clinical research Dahiya et al. Previous researches in our laboratory have demonstrated that L. Therefore, further researches were carried out and it was found that mixed lactobacilli L. However, the underlying mechanisms were unclear. Thus, in this study, the possible mechanisms by which the same lactobacilli strains could prevent obesity were mined. The anti-obesity effect of mixed lactobacilli in vivo was studied using the D high fat diet-induced obesity model, which is a widely used model for obesity research. Convincing evidence has demonstrated that obesity is often accompanied by dyslipidemia, such as elevated levels of TC, TG, and LDL-C, as well as decreased HDL-C levels, which are risk factors for cardiovascular disease Hunter and Hegele, ; Kotsis et al. Thus, after 8 weeks of animal feeding, the levels of TC, TG, LDL-C and HDL-C in the serum of the three groups of mice were measured to evaluate their blood lipid metabolism. Our data indicated that compared with the control group, the serum levels of TC, TG and LDL-C were significantly increased, and the serum levels of HDL-C were significantly decreased in the HFD group, as expected. However, such changes in mice fed a high fat diet were reversed by the mixed lactobacilli treatment, implying an improvement in metabolic dysfunction. The findings were in agreement with previous research that a probiotic L. plantarum strain isolated from the homemade kumiss could effectively inhibit serum TC, TG, LDL-C and HDL-C changes from feeding with high fat diet Wang et al. Obesity is frequently characterized by the development of non-alcoholic fatty liver disease NAFLD Michelotti et al. The liver, an important site of lipid metabolism in the body, maintains the balance of lipid synthesis and decomposition under normal conditions, whereas a high-fat diet breaks this balance, causing excessive lipid accumulation that is, hepatic steatosis and oxidative stress in the liver, indicating the occurrence of liver injury Rotman and Sanyal, ; Friedman et al. On this account, we aimed to determine the preventive effect of mixed lactobacilli intervention on NAFLD in high fat diet-fed mice. First, hepatic lipid accumulation was evaluated by measuring TG concentration. A significant elevated TG concentration in the liver was observed in the HFD group, which was consistent with the large number of lipid droplets in liver histopathological sections of the HFD group observed in our previous studies Lu J. These results were in agreement with the earlier reports in which, obese mice suffered from non-alcoholic hepatic steatosis Liou et al. However, it is noteworthy that mixed lactobacilli treatment substantially attenuated hepatic steatosis. Second, we assessed liver oxidative stress by analyzing antioxidant indices and lipid peroxidation biomarkers, including SOD, CAT, GSH-Px, GSH, and MDA. SOD, a critical antioxidant, can convert superoxide radical anions O 2 — , incompletely reduced forms of oxygen into hydrogen peroxide H 2 O 2 , which in turn is catalyzed into water by CAT and GSH-Px Turrens, ; Borrelli et al. GSH as a non-enzymatic antioxidant can directly scavenge reactive oxygen species ROS by binding with them Anu et al. MDA is the end product of free radical-mediated lipid peroxidation and is currently considered a reliable biomarker related to oxidative stress Wang et al. Our results demonstrated that oral administration of mixed lactobacilli significantly increased levels of SOD, CAT, GSH-Px, and GSH while significantly reducing MDA levels in high fat diet-fed mice, suggesting amelioration of liver oxidative stress. Finally, serum ALT and AST levels, often used to determine the extent of liver function damage Zhao et al. We found that serum levels of ALT and AST were significantly decreased in the MX group. Similarly, it has been previously stated that the treatment of the probiotic mixture 6 Lactobacillus and 3 Bifidobacterium reduced serum ALT and AST levels in high fat diet-fed rats Liang et al. Taken together, the mixed lactobacilli could inhibit liver lipid accumulation, enhance liver antioxidant capacity and improve liver function. To further explore the potential mechanisms by which mixed lactobacilli inhibited obesity induced by high fat diet in mice, we examined the expression of lipid metabolism-related genes in epididymal adipose tissue. Adipose tissue, as one of the main sites for storing triglycerides, is an important organ regulating lipid metabolism Schneeberger et al. Park et al. The AMPK pathway is a classical pathway that regulates lipid metabolism. AMPK is a known cellular energy sensor that shuts down anabolic pathways such as fatty acid synthesis Hardie and Pan, ACC and FAS are key enzymes in fatty acid synthesis Liou et al. Specifically, activation of AMPK-α stimulates ACC phosphorylation, which blocks the expression of FAS Liou et al. HSL is the rate-limiting enzyme in the breakdown of triglycerides in adipose tissue Liou et al. In the present study, the mRNA levels of AMPK-α and HSL were remarkably reduced in the HFD group compared with the control group, while the mRNA levels of ACC and FAS were significantly elevated, and these changes were completely eliminated by the treatment of mixed lactobacilli, similar to the study by Qiao et al. Qiao et al. Accumulating evidence suggests that the gut microbiota is a key environmental factor in the development of obesity Walker and Julian, For instance, a previous study showed that germ-free, lean mice transplanted with intestinal microbiota from obese mice became obese, while those transplanted with intestinal flora from lean mice remained lean Turnbaugh et al. Accordingly, gut microbiota is considered as a new target for the prevention and treatment of obesity. Subsequently, to investigate whether the mixed lactobacilli exerted its anti-obesity effects also through regulating the gut microbiota, we determined the intestinal bacteria composition of the three groups of mice. The researchers found that Firmicutes could produce more harvestable energy than Bacteroidetes, so in the case of an increase in the relative abundance of Firmicutes and a decrease in the relative abundance of Bacteroidetes, the absorption of calories increased and then promoted obesity Turnbaugh et al. At the genus level, our results reflected that the relative abundances of Bifidobacterium , Bacteroides , Alistipes , Lachnospiraceae NK4A group and Alloprevotella decreased while that of Parabacteroides , Eubacterium xylanophilum group , GCA , Lachnoclostridium , Lachnospiraceae UCG and Romboutsia increased in the HFD group compared with the control group. In line with our results, earlier studies found that the abundances of Bifidobacterium Zhu et al. Bifidobacterium , a beneficial microbial species, producing lactic acid and acetic acid, can reduce intestinal pH and inhibit the growth of various detrimental bacteria to maintain intestinal health Wang R. Bacteroides , Alistipes , Lachnospiraceae NK4A group and Alloprevotella are also capable of producing SCFAs such as acetic acid and butyric acid Borton et al. It was reported that the abundance of Bacteroides was reduced in individuals with atherosclerotic cardiovascular disease Jie et al. Alistipes can effectively inhibit inflammation via preventing LPS-induced TNF-α release at higher concentrations Canfora et al. Previous studies have indicated that Lachnospiraceae NK4A group may have an anti-inflammatory effect Li et al. Alloprevotella has been shown to be significantly reduced in mice with metabolic syndrome Shang et al. According to previous studies, Parabacteroides was enriched in individuals with type 2 diabetes Qin et al. Eubacterium xylanophilum group , GCA , Lachnoclostridium , Lachnospiraceae UCG and Romboutsia belong to Lachnospiraceae, which may suppress the growth of SCFA-producing bacteria Duncan et al. Importantly, the mixed lactobacilli treatment reversed the changes in several of the above genus. Changes in the gut microbiota cause changes in the SCFAs levels, which are negatively correlated with obesity Coelho et al. SCFAs produced by bacteria may induce the release of gut-derived satiety hormones, such as peptide YY PYY and glucagon-like peptide-1 GLP-1 , which suppress food intake and increase satiety Canfora et al. Furthermore, studies have indicated that SCFAs can reach the liver through the portal vein, thereby activating the nuclear erythroid 2-related factor 2 Nrf-2 pathway to alleviate oxidative stress Li et al. In addition, SCFAs have been reported to regulate lipid metabolism in adipose tissue by modulating related signaling pathways Gijs et al. Therefore, we determined the levels of acetic acid, butyric acid, propionic acid and valeric acid in each group by GC-MS. Intriguingly, compared to the HFD group, mixed lactobacilli supplementation significantly increased the concentrations of acetic acid and butyric acid, which was in agreement with changes in the intestinal microbiota. Based on the above results, we speculated that the mixed lactobacilli treatment might attenuate liver oxidative stress, reduce liver lipid accumulation and improve lipid metabolism of adipose tissue by regulating intestinal microbiota and metabolites. In line with our finding, Yin et al. In general, Bifidobacterium , Bacteroides , Alistipes , Lachnospiraceae NK4A group and Alloprevotella were positively correlated with acetic acid and butyric acid in intestine, AMPK-α and HSL in epididymal adipose tissue, CAT, SOD, GSH-Px and GSH in liver, and HDL-C in serum, while they were negatively correlated with ACC, FAS and PPAR-γ in epididymal adipose tissue, TG and MDA in liver, and TG, TC, LDL-C, ALT and AST in serum, but Parabacteroides , Eubacterium xylanophilum group , GCA , Lachnoclostridium , Lachnospiraceae UCG and Romboutsia displayed the opposite trend. Therefore, the results also indicated that mixed lactobacilli administration could effectively modulate the gut microbiota induced by high fat diet, and then improve obesity-related indicators. The mixed lactobacilli intervention could alleviate the changes induced by high fat diet including disordered blood lipids, liver oxidative stress and liver injury. Further, the mixed lactobacilli intervention modulated the gut microbiota of high fat diet-fed mice, resulting in increased SCFAs acetic acid and butyric acid , which regulated lipid metabolism in adipose tissue and reduced liver lipid accumulation, thereby preventing obesity. Hence, our results offer significant insight into the oral administration of mixed lactobacilli to suppress obesity in high fat diet-fed mice. The animal study was reviewed and approved by the Institutional Animal Care and Use Committee of the Northeast Agricultural University. HL did the experiments and wrote the manuscript. FL and JL did the experiments. JS, JG, and FY processed the data. BL and GH corrected the manuscript. This study was financially supported by the National Key Research and Development Program of China No. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Almalki, O. Revisional gastric bypass for failed restrictive procedures: comparison of Single-Anastomosis Mini- and Roux-en-Y Gastric Bypass. doi: PubMed Abstract CrossRef Full Text Google Scholar. Expert Panel Report: guidelines for the management of overweight and obesity in adults. Obesity 22, S41—S Google Scholar. Anu, R. Oxidative stress, prooxidants, and antioxidants: the interplay. Biomed Res. Apovian, C. Obesity 21, — Aryana, K. A year review: yogurt and other cultured dairy products. Dairy Sci. Bluher, M. Obesity: global epidemiology and pathogenesis. Borrelli, A. Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: current and innovative therapeutic approaches. Redox Biol. Borton, M. Chemical and pathogen-induced inflammation disrupt the murine intestinal microbiome. Microbiome Canfora, E. Short-chain fatty acids in control of body weight and insulin sensitivity. Gut microbial metabolites in obesity. NAFLD and T2DM. Caporaso, J. QIIME allows analysis of high-throughput community sequencing data. Methods 7, — Chang, C. Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota. Chen, Y. Wuji wan formula ameliorates diarrhea and disordered colonic motility in post-inflammation irritable bowel syndrome rats by modulating the gut microbiota. Coelho, O. Dietary fat and gut microbiota: mechanisms involved in obesity control. Food Sci. Dahiya, D. Gut microbiota modulation and its relationship with obesity using prebiotic fibers and probiotics: a review. Davidson, M. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA , — Dietz, W. Obesity and excessive weight gain in young adults: new targets for prevention. Duncan, S. Acetate utilization and butyryl coenzyme A CoA :acetate-CoA transferase in butyrate-producing bacteria from the human large intestine. Edgar, R. UPARSE: highly accurate OTU sequences from microbial amplicon reads. Methods 10, — UCHIME improves sensitivity and speed of chimera detection. Bioinformatics 27, — Friedman, S. Mechanisms of NAFLD development and therapeutic strategies. Gadde, K. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults CONQUER : a randomised, placebo-controlled, phase 3 trial. Lancet , — GBD Obesity Collaborators, Afshin, A. Health effects of overweight and obesity in countries over 25 years. Gijs, D. Short-chain fatty acids protect against high-fat diet-induced obesity via a PPARγ-dependent switch from lipogenesis to fat oxidation. Diabetes Metab. Gotoh, A. Use of Gifu Anaerobic Medium for culturing 32 dominant species of human gut microbes and its evaluation based on short-chain fatty acids fermentation profiles.

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Intensive therapy: Day 8-extended edition!

Improved lipid breakdown -
SPSS Unless indicated in the figure legends, all results were confirmed by at least three separate experiments. As shown in Fig. After liraglutide treatment for 8 weeks, serum samples and liver tissues were respectively collected for analyzing lipid parameters and lipid accumulation.

Liraglutide significantly decreased the levels of TC, TG and LDL-C similar to atorvastatin treatment. To evaluate the role of liraglutide in regulating the efflux of cholesterol from macrophages to plasma and feces, RCT was monitored in vivo.

Moreover, our data also showed atorvastatin could increase the efflux of cholesterol in vivo, which was similar to previous study [ 29 ]. Effects of liraglutide on RCT and RCT-related protein expression in mice study.

Furthermore, we investigated the effects of liraglutide on the proteins which were related to the process of RCT. However, liraglutide treatment could significantly increase ABCA1 protein expression but no change was observed in the levels of ABCG1 and SR-B1 expression Fig.

To investigate the mechanism of the effect of liraglutide on RCT in vivo, we carried out cell experiments. Firstly, we observed the effects of different concentrations of glucose and liraglutide on the activity of HepG2 cells respectively. Data showed that high glucose could reduce the viability of HepG2 cells in a dose-dependent manner Fig.

The results also showed an increased intracellular fluorescence density in a dose-dependent manner Fig. Effects of different glucose a and liraglutide b concentrations on cell viability in HepG2 cells.

Effects of different glucose concentrations on cholesterol efflux in HepG2 cells c. Effect of Liraglutide nM on cholesterol efflux in HepG2 cells under high glucose condition d.

Furthermore, the impact of liraglutide on the cell viability was examined. Data showed that liraglutide could significantly increase intracellular cholesterol efflux in HepG2 cells under high glucose condition Fig. Furthermore, we observed liraglutide could increase both gene and protein expression of ABCA1 in HepG2 cells exposed to high glucose Fig.

Effects of glucose at different concentrations 0, 5, 25, 50 mM on ABCA1, ABCG1 and SR-B1 gene a and protein b expressions in HepG2 cells. Effects of liraglutide nM on ABCA1, ABCG1 and SR-B1 gene c and protein d expressions in HepG2 cells under high glucose HG, 50 mM condition.

Under high glucose HG, 50 mM condition, U reduced the increased ABCA1 expression induced by liraglutide in HepG2 cells c. Moreover, results also showed that liraglutide significantly reduced lipid deposition in the liver in vivo.

In fact, DM is characterized by both glucose and lipid disorders. Evidence also support the notion that DM has higher rate of ASCVD and worse clinical outcomes due to the interaction of high glucose and dyslipidemia. Meanwhile, serum lipid levels including TC, LDL-C and TG in diabetic mice fed with HFD were significantly higher than those fed with ND in diabetic mice and WT mice.

More importantly, a marked inhibition of cholesterol efflux and the increased accumulation of lipid were also stably found, indicating that our model was suitable for further study regarding the impact of liraglutide on these pathophysiologic changes in the diabetic model.

As we know, liraglutide, a novel anti-diabetic medication, has recently become the first-line treatment for DM [ 33 , 34 , 35 ]. Previous studies have suggested that liraglutide exerts hypoglycemic effects by increasing insulin secretion, improving islet cell function, decreasing food intake, and reducing body weight [ 36 ].

In addition to down- regulation of the blood glucose, it also has the beneficial effects on the cardiovascular system [ 37 ]. A recent study showed that liraglutide had a cardiovascular protective effect in the type 2 diabetic patients presenting as a significant reduction of the cardiovascular events during a long-term follow-up [ 38 ].

Although the exact mechanism of this protective impact on cardiovascular system by liraglutide is currently not well determined, several animal and human observations have found that it may be associated with its reduction of body weight, recovery of liver lipid deposition, and reversal of hepatic steatosis [ 39 , 40 , 41 ].

Furthermore, the present study showed that liraglutide reduced the levels of TC, TG, and LDL-C in diabetic mice fed with HFD mediated by enhancing RCT. It has been reported that RCT is a key process involving in the lipid metabolism and cardiovascular system protection.

Hence, we hypothesized that the cardiovascular protective effects by liraglutide may be linked with RCT. That is the reason why we perform such study.

Previous study has shown that GLP-1 may affect cholesterol homeostasis by regulating the expression of miR and ABCA1 in HepG2 cells [ 42 ]. In addition, GLP-1 treatment significantly increased the expression of ABCA1, ABCG1 and LXR-α, and improved cholesterol efflux from 3T3-L1 adipocytes [ 43 ].

In addition, several studies have indicated that liraglutide can induce body weight loss through reducing food intake, promoting satiety, and inducing autophagy [ 44 , 45 , 46 , 47 ].

At the same time, we also observed that liraglutide could modify TC and TG in diabetic mice, and improve hepatic lipid accumulation. Data indicated that the hepatoprotective effects of liraglutide appeared from its direct impact rather than its glucose lowering ability.

Several recent studies have also showed that liraglutide can alleviate non-diabetes steatohepatitis. Ipsen et al. found that liraglutide significantly decreased hepatic inflammation, liver injury and hepatocyte ballooning in advanced lean non-alcoholic steatohepatitis in guinea pigs induced by high-fat diet [ 48 ].

The study by Zhang et al. demonstrated that liraglutide had a protective effect on carbon tetrachloride CCl 4 -induced acute liver injury in mice, which significantly ameliorated the liver histopathological changes, reduced hepatocyte apoptosis, and enhanced mitochondrial respiratory functions [ 49 ].

Similarly, Milani et al. found that the hepatoprotective and therapeutic effects of liraglutide on acute liver injury in mice induced by CCl 4 might be attributable to a decrease in liver oxidative stress and the preservation of metabolism [ 50 ].

Therefore, it might be concluded that the potential hepatoprotective effect of liraglutide was beyond its glucose-lowering action. Gorgani-Firuzjaee et al. showed that high glucose can induce de novo synthesis of cholesterol and VLDL production in HepG2 cells [ 52 ].

Pang et al. have found that long-term exposure of HepG2 cells to high glucose can induce reactive oxygen species ROS accumulation and DNA damage [ 53 ].

Do et al. have reported that high glucose can induce lipid accumulation in HepG2 cells [ 54 ]. It should be mentioned that signal transduction pathway regarding the role of liraglutide in regulating RCT is currently unclear although we found a beneficial impact of liraglutide on RCT in animal.

As described in the section of introduction, there are at least three key mediators ABCA1, ABCG1 and SR-B1 involving in RCT process. In order to explore which mediator is mainly associated with the RCT by liraglutide, we established a high glucose-stimulated HepG2 cell model.

By using this model, we confirmed the exact role of liraglutide in enhancing cell cholesterol efflux. We subsequently examined the effects of liraglutide on the expression of the mediators ABCA1, ABCG1 and SR-B1 and related signaling pathways.

Our findings may be an important complementary information concerning the relation of liraglutide to lipid metabolism. These results may widen our knowledge regarding the role of liraglutide in cardiovascular medicine beyond its glucose-lowering action.

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Krause GC, Lima KG, Dias HB, et al. Liraglutide, a glucagon-like peptide-1 analog, induce autophagy and senescence in HepG2 cells. Eur J Pharmacol. Studies have shown that decreased PGC-1α mRNA is associated with insulin resistance 23 , The Sirtuin family has become known as a key regulator of the nutrient-sensitive metabolic regulatory pathway Activation of SIRT1 promotes β-oxidation of fatty acids, prevents diet-induced nonalcoholic fatty liver disease, and reduces insulin resistance 26 , 27 , Obesity reduces SIRT1 activity in liver and adipose tissue 29 , Increased expression of PGC-1α and SIRT1 promotes the browning of white adipose tissue and ameliorates obesity and metabolic disorders 23 , Coenzyme Q10 CoQ 10 is a fat-soluble micronutrient synthesized in nearly all human cells and plays a role in electron transport in the mitochondrial respiratory chain 32 , CoQ 10 content in organs is gradually decreased with age and this decline is closely associated with the occurrence and development of various diseases Therefore, intake of exogenous CoQ 10 could help prevent the occurrence and progression of age-related diseases such as cardiovascular disease, metabolic syndrome, diabetes mellitus, cardiac dysfunction, and neurodegenerative diseases 35 , 36 , 37 , CoQ 10 is enzymatically maintained in its reduced form CoQ 10 H 2 and also acts as a fat-soluble antioxidant to potently protect lipid membranes and lipoproteins from oxidative damage and to prevent DNA damage 39 , 40 , Our previous studies showed that CoQ 10 H 2 increases cAMP and enhances the activity of SIRT1 and PGC-1α, thereby improving mitochondrial function and inhibiting oxidative stress In addition, other studies have shown that CoQ 10 H 2 content in adipose tissue gradually decreased with the development of obesity in both mice and humans, and that CoQ 10 H 2 synthesis-related enzymes were upregulated as a compensatory measure CoQ 10 H 2 also inhibits adipocyte differentiation and cholesterol synthesis 44 , but the mechanism remains unclear.

The present study shows that dietary supplementation of KKAy mice, a widely used model of diabetes and obesity, with CoQ 10 H 2 inhibited weight gain and reduced white adipose tissue content while enhancing brown adipose tissue function, and increasing the metabolic rate.

CoQ 10 H 2 treatment also increased expression of Sirt1 , Pgc-1α and Pparα , enhanced mitochondrial function and promoted β-oxidation of fatty acids in the liver, as well as increased levels of intracellular cAMP. Our results demonstrate that dietary CoQ 10 H 2 can suppress lipid accumulation and mitigate metabolic dysfunction.

In this study, dietary supplementation with CoQ 10 H 2 was employed to investigate the effect of CoQ 10 H 2 on metabolic syndrome in KKAy mice. Every week, all mice were weighed and food intake was calculated. CoQ 10 H 2 prevented the accumulation of visceral fat iWAT in KKAy mice and protected mice from insulin resistance and metabolic disorders.

A — C Body weight and iWAT content changes for animals in the control and CoQ 10 H 2 groups. In addition, inguinal white adipose tissue iWAT was significantly reduced and percent adipose tissue was lower in KKAy mice supplemented with CoQ 10 H 2 compared with the control group Fig.

The occurrence and development of obesity are often associated with abnormal lipid and glucose metabolism. Therefore, we next addressed whether CoQ 10 H 2 can improve metabolic function.

Serum total cholesterol and triglyceride content were significantly decreased in KKAy mice given CoQ 10 H 2 supplementation Fig.

CoQ 10 H 2 also reduced concentrations of fasting blood glucose and serum insulin in KKAy mice Fig. In addition, mice with CoQ 10 H 2 supplementation also showed better glucose tolerance in an intraperitoneal glucose tolerance test IPGTT Fig.

Together, these results indicate that CoQ 10 H 2 can control obesity and improve insulin resistance in KKAy mice. Obesity in KKAy mice was primarily caused by hypertrophy of adipocytes, while CoQ 10 H 2 supplementation significantly prevented this adipocyte hypertrophy.

Expression levels of several marker genes for fatty acid synthesis e. BAT is involved in regulation of energy metabolism and obesity.

Activation of BAT can burn fatty acids to produce heat, reduce triglyceride content, and inhibit obesity KKAy mice in the control group had more abundant and larger lipid droplets in BAT, while CoQ 10 H 2 supplementation inhibited the excessive accumulation of lipid droplets in BAT.

BAT thermogenesis induces expression of uncoupling protein 1 Ucp1 and other genes, promoting lipolysis, mitochondrial biogenesis, and β-oxidation of fatty acids. Our experiment showed that mRNA expression of Ucp1 and other thermogenesis-related genes was significantly increased in BAT from KKAy mice supplemented with CoQ 10 H 2 compared with the control group, suggesting that the CoQ 10 H 2 group had increased BAT thermogenic activity Fig.

CoQ 10 H 2 inhibited lipid accumulation in iWAT and promoted BAT function. After differentiation, mature adipocytes were round and contained a large number of lipid droplets Day 5. Compared with the control group, the addition of CoQ 10 H 2 before differentiation inhibited adipocyte differentiation and the accumulation of fat.

Also, the addition of CoQ 10 H 2 to differentiated adipocytes reduced the cellular lipid content and promoted lipolysis on Day 5 and Day 10, respectively, after initiating treatment. Taken together, our results demonstrate that CoQ 10 H 2 improves lipid metabolism and inhibits obesity in KKAy mice.

The liver plays an important role in the digestion, absorption, synthesis, and decomposition of lipids CoQ 10 H 2 improves cAMP levels and promotes lipid metabolism in the livers of KKAy mice. Histograms show fold-change in mRNA level relative to week-old control KKAy mice.

All blots were obtained under the same experimental conditions, and cropped images of the blots are shown. Densitometric quantification is depicted on the right panel.

In addition, CoQ 10 H 2 treatment increased expression of Sirt1 , Pgc-1α and Pparα , enhancing mitochondrial function and promoting the β-oxidation of fatty acids, and simultaneously decreased expression of Serbp1c , Fas and Pparγ , thereby inhibiting de novo synthesis of fatty acids Fig.

AMP-activated protein kinase AMPK acts as an energy sensor to help maintain cellular energy homeostasis; AMPK activation inhibits the accumulation of liver lipids in type 2 diabetic mice and has beneficial effects against hyperlipidemia and atherosclerosis 47 , We assessed hepatic AMPK activity in KKAy mice by measuring the phosphorylation status of AMPK and Acetyl-CoA carboxylase ACC.

We found that hepatic AMPK activity was significantly increased in mice receiving CoQ 10 H 2 supplementation compared with controls Fig. cAMP is a second messenger that regulates the activity of SIRT1 and AMPK and is involved in regulation of intracellular energy metabolism 49 , We found that dietary supplementation with CoQ 10 H 2 significantly increased hepatic cAMP content in KKAy mice Fig.

As a second messenger coupled to G-protein pathways, cAMP concentrations can change rapidly. As such, we measured the change in cAMP content in HepG2 cells 0.

Adenylyl cyclase AC is responsible for intracellular cAMP synthesis and MDLA is a specific inhibitor of AC. Addition of exogenous CoQ 10 H 2 to cultured HepG2 cells increased intracellular cAMP but was not inhibited by MDLA Fig.

These results showed that the increased intracellular cAMP induced by CoQ 10 H 2 is not due to increased cAMP synthesis. CoQ 10 H 2 inhibits expression of PDE4 in the liver by decreasing C-FOS binding to the PDE4 promoter.

A Liver cAMP concentrations of KKAy mice in the control and CoQ 10 H 2 groups at ages 12, 16, and 20 weeks. Histograms show fold-change of the mRNA level relative to untreated control cells.

Phosphodiesterases PDEs are encoded by 21 genes that are divided into 11 families according to their structural similarity.

PDEs regulate cellular signal transduction by specifically hydrolyzing cAMP e. PDE1, 5, 6, 9 and 10 In addition, gene expression of PDEs has significant tissue specificity e. Measurement of the expression of each cAMP-specific PDE subtype showed that PDE4A and PDE4C expression was reduced in HepG2 cells with CoQ 10 H 2 addition Figs S2 and 4D.

We also confirmed that CoQ 10 H 2 reduced the protein content of PDE4 in HepG2 cells and the liver of KKAy mice Fig. To demonstrate whether CoQ 10 H 2 can directly inhibit PDE activity, we constructed Lineweaver-Burk plots to express the relationship between PDE activity and CoQ 10 H 2 treatment.

These data indicate that CoQ 10 H 2 enhanced intracellular cAMP concentrations by inhibiting PDE4 gene expression rather than activity. Activating protein-1 AP-1 , a mammalian transcription factor, is not a single protein, but a homologous or heterologous complex consisting of proteins from the Fos and Jun families In this study, mRNA levels of the AP-1 component C-FOS but not C-JUN Fig.

S3 and C-FOS phosphorylation were significantly reduced by CoQ 10 H 2 Fig. Next, we investigated the regulatory effect of AP-1 on the expression of PDE4 using chromatin immunoprecipitation Fig.

These data suggest that CoQ 10 H 2 regulates binding of AP-1 to the PDE4 promoter, thereby reducing PDE4 levels and inhibiting cAMP hydrolysis. Densitometric quantification is depicted in the right panel.

It is well known that CoQ 10 H 2 is a powerful antioxidant that can potently inhibit the generation of oxygen free radicals and oxidative stress damage, thereby ameliorating age-associated disease.

This effect has been shown both in mouse and cell experiments Obesity is a chronic metabolic disease caused by various factors including heredity, environment, dietary patterns, and living habits, and the development of obesity is accompanied by decreased CoQ 10 H 2 content in adipose tissue, as seen in both human and mouse models 43 , At the same time, increased CoQ 10 H 2 synthesis can ameliorate metabolic disorders and insulin resistance caused by obesity, and significantly inhibits 3T3L1 preadipocyte differentiation and lipid accumulation Therefore, we hypothesized that CoQ 10 H 2 might regulate lipid metabolism to some extent.

As a widely used model of obesity and type 2 diabetes, KKAy mice develop obesity and insulin resistance accompanied by hepatic steatosis at an early age In our study, the development of obesity in KKAy mice was inhibited by administration of exogenous CoQ 10 H 2 , while food intake was not changed Fig.

At the same time, accumulation of visceral fat was inhibited Fig. As a model of insulin resistance, fasting blood glucose in KKAy mice is high and is gradually increased with the aggravation of obesity.

These phenomena are potently reversed by CoQ 10 H 2 supplementation Fig. Analysis of various lipid metabolism markers in iWAT and BAT revealed that CoQ 10 H 2 can inhibit de novo synthesis of fatty acids and promote oxidation of fatty acids Fig.

To determine if CoQ 10 H 2 affects adipogenesis and lipolysis, we added CoQ 10 H 2 to pre-adipocyte 3T3L1 cultures before and after differentiation into mature adipocytes. Our results demonstrate that CoQ 10 H 2 reduces adipose differentiation and lipid storage in adipocytes.

The liver is the main site of lipid metabolism and lipid metabolism disorders caused by obesity are a major cause of non-alcoholic fatty liver disease. Significant hepatic steatosis occurred in the livers of KKAy mice in the control group, while the livers of mice supplemented with CoQ 10 H 2 did not show obvious changes Fig.

PGC-1α is a transcriptional coactivator that is closely related to energy metabolism and plays an important role in the process of mitochondrial synthesis and adaptive thermogenesis 59 , PGC-1α is also involved in glucose and lipid metabolism, and has become a new target for the treatment of diabetes, obesity, and other metabolic diseases Supplementation with CoQ 10 H 2 increased PGC-1α gene expression in the liver Fig.

Previous results have shown that expression and activity of PGC-1α are regulated by AMPK and SIRT1 AMPK is an essential protein kinase involved in the regulation of energy metabolism in vivo.

Activation of AMPK can inhibit ATP-consuming pathways, such as the synthesis of fat and cholesterol, and promote ATP-forming pathways, such as β-oxidation of fatty acids In a model system, decreased AMPK activity resulted in insulin resistance and activation of AMPK-enhanced insulin sensitivity 62 , 63 , In addition, AMPK activation was also directly involved in regulating the activity of fat metabolism-related factors, such as SREBP1c SIRT1 is widely known for its anti-aging effect SIRT1 also plays an important role in cellular energy metabolism It directly regulates the expression and activity of PPAR family genes and participates in the regulation of lipid metabolism pathways In addition, SIRT1 can also deacetylate the AMPK upstream kinase LBK1 and activate AMPK In KKAy mice, SIRT1 protein content and AMPK activity decrease with age, and this effect is ameliorated by CoQ 10 H 2 supplementation Fig.

The second messenger cAMP plays a key role in transduction of various extracellular signals in cells. Our previous work demonstrated that CoQ 10 H 2 increases cAMP content in the liver and regulates lipid metabolism in mice These results were confirmed in the present study Fig. We found that specific inhibition of PDE4 expression in cultured cells increased cAMP Fig.

Interestingly, as shown in Fig. We further demonstrated that CoQ 10 H 2 inhibited transcriptional activity of the transcription factor AP-1 and that of C-FOS, a component of AP-1, and that CoQ 10 H 2 inhibited the ability of AP-1 to bind to the PDE4 gene promoter Fig.

Similarly, dietary supplementation with CoQ 10 H 2 inhibited SERCA2 damage induced by obesity in KKAy mice Fig. Furthermore, by inhibiting the ability of AP-1 to bind the PDE4 promoter, expression of PDE4 was inhibited and intracellular cAMP was increased.

The de novo synthesis of fatty acids was inhibited and β-oxidation of fatty acids was enhanced due to CoQ 10 H 2 -induced alterations in the activity of factors such as AMPK and PGC-1α.

CoQ 10 H 2 supplementation also inhibited the accumulation of fat in adipose tissue, promoted fat mobilization, and reduced body weight Fig.

In conclusion, our results suggest that CoQ 10 H 2 could serve as a safe and effective supplement to improve lipid metabolism and insulin resistance in the future.

Proposed mechanism by which CoQ 10 H 2 improves metabolic function and inhibits insulin resistance in KKAy mice. PDE4 gene expression was then inhibited and intracellular cAMP was increased. The increase in cAMP, however, promoted AMPK activity. On the one hand, expression of SIRT1 and PGC-1α was increased and mitochondrial function was enhanced to promote the decomposition of fatty acids.

On the other hand, triglyceride and cholesterol biosynthesis was inhibited. In adipose tissue, CoQ 10 H 2 can prevent the excessive accumulation of visceral fat and promote the function of BAT, thereby improving obesity, insulin resistance, and metabolic syndrome.

The mice were randomly distributed into two experimental groups. Body weight and serum triglyceride and total cholesterol levels were determined and no statistically significant differences were found between the two groups at baseline data not shown.

Animals were fed either CoQ 10 H 2 -supplemented feed final concentration of 0. All mice were allowed free access to food and water, and body weight was recorded and food intake calculated twice a week.

Mice were examined daily. Blood glucose levels were measured using Accu-Chek Aviva glucose monitors Roche, Indianapolis IN. To determine serum levels of insulin, triglyceride and total cholesterol, blood samples were collected from the heart during dissection and stored in test tubes.

All experiments using animals were performed with the approval of the Committee for Animal Experiments of Shinshu University and approved protocols were strictly followed. Permit number: from The human hepatoma HepG2 cell line was provided by the RIKEN BRC through the National Bio-Resource Project of the MEXT, Japan, and 3T3L1 cells were purchased from the Japanese Cancer Research Resources Bank.

Cells were then collected with a scraper. Refer to the supplementary data for the experimental protocol for 3T3L1 cells. Tissues and cells were lysed in cell lysis buffer Cell Signaling Technology, MA supplemented with protease inhibitors Sigma Aldrich, MO. Supernatants were collected, and protein concentrations were determined using the BCA protein Assay Kit Thermo Fisher Scientific, CO.

Target proteins were detected with the enhanced chemiluminescence ECL system and quantified using a densitometric image analyzer with Image-Pro Plus 4.

The mixture was rotated in a 1. Total RNA was extracted using TRIzol Reagent Invitrogen, CA , followed by treatment with DNA-Free Applied Biosystems, CA to remove contaminating DNA and then subjected to reverse transcription using an Omniscript RT kit Applied Biosystems, CA with random primers Applied Biosystems, CA.

Quantitative real-time RT-PCR analysis was carried out using an ABI PRISM Sequence Detection System Applied Biosystems, CA with SYBR Green Takara Bio, Tokyo, Japan. Primer sequences are listed in Supplementary Table 1. Blanks for spontaneous cAMP hydrolysis contained the corresponding buffer.

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a State Key Laboratory of Food Pure herbal focus enhancer and Technology, Nanchang Breakdowwn, NanchangChina E-mail: zlzengjx hotmail. ImprocedPerformance recovery nutrition bfeakdown b Jiangxi Province Key Micronutrient absorption in the gut of Edible Improved lipid breakdown Medicinal Resources Exploitation, Nanchang University, NanchangChina. c School of Chemistry and Chemical Engineering, Nanchang University, NanchangChina. d School of Food Science and Technology, Nanchang University, NanchangChina. e School of Resource and Environmental, Nanchang University, NanchangChina. f New Zealand Institute of Natural Medicine Research, 8 Ha Crescent, AucklandNew Zealand. Improved lipid breakdown

Lioid gut microbiota is Performance recovery nutrition central regulator of host Performance recovery nutrition. Lipkd composition and Cholesterol level and diet recommendations of the gut microbiota Breakvown dynamic and Performance recovery nutrition by diet properties such as the breakdonw and composition of lipids. Hence, dietary lipids may influence host physiology through interaction with the gut microbiota. Lipids affect the gut microbiota both as substrates for bacterial metabolic processes, and by inhibiting bacterial growth by toxic influence. The gut microbiota has been shown to affect lipid metabolism and lipid levels in blood and tissues, both in mice and humans.

Improved lipid breakdown -
The lard diet also promoted a shift in gut microbiota composition and functions, including changes with potential impact on lipid and amino acid metabolism.

The mechanisms by which dietary fatty acids affect gut microbiota are not well defined. Although most of the fatty acids consumed are absorbed in the small intestine, a minority will pass through the gastrointestinal tract and may therefore directly modulate colonic microbiota composition. Fatty acids have a broad spectrum of antibacterial activity including lysis and solubilization of bacterial cell membranes [ 14 , 15 ] and inhibition of ATP production [ 16 ].

The antibacterial action of fatty acids is affected by carbon chain length, saturation and double bond position [ 17 ]. However, the impact of fatty acids on the gut microbiota is not limited to antibiotic action. Although gut anaerobes cannot produce energy by beta-oxidation, bacteria can metabolize fatty acids through other pathways.

For example, in a mouse model of alcoholic liver disease, ethanol was found to inhibit biosynthesis of saturated fatty acids by the intestinal microflora. Dietary supplementation with saturated long-chain fatty acids, which were metabolized by and promoted growth of Lactobacillus, reversed alcohol-induced dysbiosis, stabilized the intestinal gut barrier, and reduced liver injury [ 18 ].

Intestinal bacteria can also react with fatty acid double bonds to produce metabolites that cannot be synthesized by mammalian hosts. Bacterial processing of linoleic acid, for example, has been shown to produce metabolites that may influence host physiology and health. Conjugated linoleic acid CLA can be produced by several gut bacteria including Lactobacillus, Butyrivibrio, and Megasphaera [ 19 , 20 ].

Different CLA isomers have been demonstrated to have different, and sometimes opposite, effects on the host: c9,tCLA improves insulin sensitivity and decreases atherosclerosis by activation of proliferator-activated receptor γ PPARγ , t10,cCLA worsens insulin sensitivity and atherosclerosis by inhibiting expression of PPARγ and LXRα [ 21 , 22 , 23 ], and t9,tCLA reduces atherosclerosis by activation of LXRα [ 24 ].

Different bacteria produce different ratios of CLA isomers [ 25 , 26 ] and promotion of bacteria that produce high levels of beneficial CLAs could therefore potentially be used to promote a healthy metabolic phenotype. Bacterial production of CLAs is a multistep process involving several metabolic intermediates.

These metabolites include several hydroxy fatty acids that affect processes related to host health. Another hydroxylated CLA intermediate - oxo-cisoctadecenoic acid KetoA - increases adiponectin production and glucose uptake in a PPARγ-dependent manner, and contributes to the prevention of obesity-related metabolic perturbations [ 28 ].

Studies in gnotobiotic mice have shown that the gut microbiota affects host lipid metabolism. Importantly, GF mice are protected against diet-induced obesity through a combination of several mechanisms including increased fatty acid oxidation and decreased deposition of triglycerides in adipocytes compared to CONV-R mice [ 29 ].

Furthermore, lipidomics analysis of GF and CONV-R mice fed a regular chow diet showed that the gut microbiota affects lipid composition in host tissues and serum and increases clearance of triglycerides from the circulation [ 30 ].

In contrast, circulating triglycerides, HDL, and total cholesterol levels are increased by the gut microbiota in mice on a high-fat diet [ 31 ]. Comparisons between CONV-R and GF mice have also shown that the gut microbiota induces hepatic production of monounsaturated fatty acids and elongation of PUFA, and that acetate produced by the gut microbiota is used as precursor in hepatic fatty acid synthesis [ 32 ].

The gut microbiota affects host lipid metabolism and lipid composition through interaction with the diet. In a recent study by Just et al, CONV-R and GF mice were fed palm oil or lard diet both rich in saturated lipids supplemented with bile acids [ 11 ].

They found that the gut microbiota increased hepatic triglycerides and cholesteryl esters levels only in mice fed lard, and that colonization status had a major impact on hepatic lipids. In another study where CONV-R and GF mice were fed lard or fish oil diet it was also found that the microbiota downregulates cholesterol biosynthesis and increased hepatic levels of cholesterol specifically in mice fed lard [ 33 ].

However, in this study the relative contribution of the gut microbiota to the total variation in the hepatic lipid dataset was small and no serum lipids differed significantly between CONV-R and GF mice.

This discrepancy between the two studies could possibly be attributed to the relative similarity between palm oil and lard compared to fish oil and lard. Studies in mice treated with probiotics provide further evidence for a role of the gut microbiota in regulation of host lipid homeostasis.

In mice fed a high-fat high-cholesterol diet, Lactobacillus curvatus alone or together with Lactobacillus plantarum reduced cholesterol in plasma and liver and the two strains had a synergistic effect on hepatic triglycerides [ 34 ].

Similarly, in obese rats fed a high-fat diet, Bifidobacterium spp. decreased levels of circulating triglycerides and LDL and increased levels of HDL [ 35 ].

Overall, studies in mouse models show that the gut microbiota, in concert with the diet, regulates host lipid metabolism and lipid levels in serum and tissues. The fecal microbiota has also been linked to lipid metabolism in humans.

Taxonomy and functional profiles of the bacteria differ between obese and lean subjects, but results from different studies are inconsistent, in part because of the complex nature of obesity but also because different methods have been used to analyze the microbiota [ 36 ].

A number of studies have investigated the association between the gut microbiota and dyslipidemia. When profiling metagenomics data from obese individuals, Cortillard et al found that reduced total microbial gene richness was associated with increased total serum cholesterol and serum triglycerides in obese patients.

An energy-restricted diet intervention increased microbial gene richness and reduced serum lipids [ 37 ]. Similarly, Le Chantelier et al showed that triglycerides were higher and HDL levels were lower in individuals with low microbial gene counts than in those with high microbial gene counts [ 38 ].

Changes in fecal microbiota composition are also present in individuals with pathophysiological conditions associated with dyslipidemia and ectopic fat deposition such as atherosclerosis and fatty liver. By analyzing the microbial composition of atherosclerotic plaques, fecal samples and the oral cavity in patients with symptomatic carotid artery stenosis [ 40 ], Koren et al observed shared operational taxonomic units OTUs between all three sites, consistent with the possibility that oral and gastrointestinal microbiota might be involved in inflammatory processes responsible for atherosclerosis.

OTUs attributed to Fusobacterium from the oral cavity correlated with total serum cholesterol and LDL, and Streptococcus OTUs correlated with HDL levels. However, there was no clear fecal microbial signature that could distinguish between patients and controls [ 40 ].

In contrast, Karlsson et al showed that individuals with symptomatic atherosclerosis had higher abundance of the genus Collinsella and lower abundance of Eubacterium and Roseburia compared with healthy controls.

Functionally, the gut microbiome of patients had increased capacity for peptidoglycan synthesis, which might contribute to the chronic inflammation in the atherosclerotic arterial walls [ 41 ].

Another study found an association between coronary artery disease CAD and gut microbiota composition by demonstrating that the phylum Bacteroidetes was decreased and the order Lactobacillales was increased in CAD patients compared to both subjects with coronary risk factors but without CAD and healthy controls [ 42 ].

Several studies have shown that the fecal microbiota composition in subjects with NAFLD differs from that of healthy controls and obese patients without fatty liver disease [ 43 , 44 , 45 ].

Hoyles et al recently show that patients with steatosis have decreased microbial gene richness and altered genetic potential for several functions including the processing of dietary lipids [ 46 ]. Furthermore, changes in fecal microbiota composition have been shown to associate with the severity of NAFLD and its progression to fibrosis and non-alcoholic steatohepatitis NASH [ 47 , 48 ].

An increased abundance of Bacteroidetes in patients with fibrosis or NASH is the most consistent finding in these studies.

Short-chain fatty acids SCFAs such as acetate, propionate and butyrate are bacterial metabolites derived from fermentation of fibers in the colon Fig.

Both butyrate and propionate have low systemic concentrations whereas acetate levels are higher [ 49 ]. SCFAs are important for host metabolism and are used as substrates for energy production, lipogenesis, gluconeogenesis and cholesterol synthesis [ 50 , 51 ]. Butyrate is an energy source for colonocytes while propionate is mainly metabolized by the liver.

Mechanisms linking the gut microbiota to lipid metabolism and pathophysiological conditions associated with dyslipidemia.

Short-chain fatty acids regulate host lipid metabolism by supplying the host with energy, improving peripheral tissue metabolism and stimulating incretin hormone production.

The gut microbiota transforms choline and L-carnitine to trimethylamine TMA. TMA is transformed into trimethylamine N-oxide TMAO that may promote increased atherosclerosis through mechanisms related to lipid metabolism and inflammation. Bile acids regulate metabolism by binding to farnesoid X receptor FXR and G protein-coupled bile acid receptor 1 TGR5 in several different tissues.

Deconjugation of bile acids reduces absorption and increase excretion of bile acids. Increased gut permeability facilitates translocation of lipopolysaccharide LPS over the intestinal epithelium. LPS induce inflammation through TLR4 that may result in metabolic perturbations and contribute to development of metabolic diseases.

HDL may neutralize the toxic effect of LPS. PPARγ, peroxisome proliferator-activated receptor gamma; GPR43, G-protein coupled receptors GPR43 FFAR2 ; GPR41, G-protein coupled receptors GPR43 FFAR3 ; SCFA, short-chain fatty acid; PYY, peptide YY; TLR4, toll-like receptor 4.

GPR43 protects against diet-induced-obesity in mice [ 52 , 53 , 54 , 55 ]. Activation of GPR43 on L-cells increases secretion of glucagon-like peptide-1 GLP-1 [ 52 , 56 ] and acetate induces anti-lipolytic activity [ 57 ] and improves glucose and lipid metabolism [ 53 ] through GPR43 in WAT.

GRP41 has also been shown to regulate metabolism through interaction with the gut microbiota. CONV-R Gpr41 knockout mice are leaner and weigh less than their wild-type littermates, while these differences are not found in GF mice.

Furthermore, the microbiota increases peptide YY PYY production through GPR41 [ 58 ]. Butyrate and propionate have also been shown to activate PPARγ [ 59 ], and SCFA-induced activation of PPARγ modulates lipid metabolism through increased energy expenditure [ 60 ], reduced body weight and decreased liver triglyceride accumulation [ 61 ].

Overall, SCFAs have been shown to have a positive impact on metabolic health [ 62 ]. Supplementation with acetate reduces weight gain and improves glucose tolerance in obese and diabetic rats [ 63 ], butyrate protects against obesity and increases thermogenesis in mice [ 60 ] and propionate or butyrate improves glucose homeostasis in mice [ 64 ].

Some minor clinical trials have also found beneficial effects of SCFA or fiber supplementation on body weight [ 56 , 65 ]. Ingestion of a propionate precursor increases postprandial plasma PYY and GLP-1 and reduces energy intake while long-term treatment results in a reduction in weight gain [ 56 ].

Plasma concentrations of PYY and GLP-1 are also increased by acetate in humans [ 66 ]. Primary bile acids are synthesized from cholesterol and conjugated to taurine or glycine in the liver. The bile acids are stored in the gallbladder and excreted into the duodenum after food ingestion to aid emulsification of dietary lipids.

Most of the bile acids are reabsorbed and recirculated to the liver, but bacterially mediated deconjugation of the glycine or taurine group reduces reabsorption. Deconjugated bile acids can be further metabolized to secondary bile acids through dehydrogenation, dehydroxylation and epimerization by colonic bacteria [ 67 ].

Microbial processing results in a more hydrophobic bile acid pool and facilitates excretion in the feces. Fecal excretion of bile acids is a major sink for cholesterol and bile acids lost in the process need to be replaced by de novo synthesis from cholesterol [ 67 ]. In addition to their role in lipid digestion, bile acids can act as signaling molecules that regulate host metabolism by binding to the nuclear receptor farnesoid X receptor FXR and the Takeda G-protein coupled bile acid receptor TGR5.

Microbial processing of bile acids increases the diversity of the bile acid pool and the different bile acids vary in their affinity to the receptors and can act as agonists or antagonists.

Both of the primary bile acids cholic acid CA and chenodeoxycholic acid CDCA and the secondary bile acids lithocholic acid LCA and deoxycholic acid DCA are FXR agonists, but with different affinities [ 68 ]. In humans, CDCA can be transformed into ursodeoxycholic acid UDCA , which is a FXR antagonist [ 69 ].

Furthermore, the taurine-conjugated murine bile acid TβMCA, but not its deconjugated counterpart βMCA, is a potent FXR antagonist [ 70 ]. FXR is involved in the regulation of lipid metabolism, especially triglyceride trafficking, synthesis and utilization [ 71 ].

Microbial processing of bile acids may therefore influence lipid metabolism through interaction with FXR. By feeding wild-type and Fxr knockout mice with or without bacteria a high-fat diet, Parséus et al showed that microbiota-induced weight gain, steatosis and inflammation were dependent on FXR signaling [ 72 ].

FXR also changed the gut microbiota composition, and transplantation of the gut microbiota into GF mice transferred the lean phenotype of Fxr knockout donor mice, demonstrating that FXR may contribute to increased adiposity by altering the microbiota composition.

Comparison of whole body and tissue-specific Fxr knockout mice have revealed that activation of the liver and intestinal FXR result in distinct metabolic outcomes in obesity models [ 73 , 74 , 75 , 76 , 77 ].

Several studies indicate that inhibition of intestinal FXR improves metabolic phenotypes [ 75 , 77 ] but the underlying mechanisms are still unknown. Bile acids have also been shown to influence host lipid metabolism through TGR5. TGR5 activation in skeletal muscle and brown adipose tissue promotes energy expenditure [ 78 ].

In addition, TGR5 signaling induces GLP-1 release from enteroendocrine L-cells, resulting in improved liver and pancreatic function in obese mice [ 79 ], with potential influences on lipid synthesis and storage. The microbially produced bile acids LCA and DCA act as agonists to TGR5 [ 78 , 80 ] but the impact of the gut microbiota on host metabolism via TGR5 remains to be determined.

Bile acids have been implicated in the pathogenesis of fatty liver disease. Patients with NASH have been shown to have altered fecal bile acid composition [ 81 ]. In addition, an inverse relation between fibroblast growth factor 19 FGF19 , an FXR-regulated hormone produced in the ileum, and NASH has been reported [ 82 , 83 ].

The importance of understanding the interplay between the gut microbiota, bile acids and lipid homeostasis is highlighted by efforts to use bile acids as treatments for NAFLD and NASH. One example is UDCA, which has been shown to have beneficial impact on steatosis and serum lipid levels after short-term treatment in severely obese patients [ 69 ] while others have reported negative results regarding improvement of NASH in response to UDCA treatment [ 84 , 85 ].

However, accompanying elevations in serum LDL levels have raised the question of the overall benefit of such treatment. Short-term treatment with the FGF19 analog NGM resulted in reduction of steatosis in NASH patients [ 87 ].

To date, no clinical study targeting the gut microbiota to specifically modify FXR signaling in NAFLD or NASH has been performed. Lipopolysaccharides LPS , also known as endotoxins, are structural compounds in the outer membrane of Gram-negative bacteria.

LPS induces inflammation through activation of TLR4, which is expressed on immune cells such as macrophages as well as on many other cell types including hepatocytes and adipocytes.

The intestinal epithelium works as a barrier to prevent translocation of bacterially derived factors. However, weight gain, high-fat diet [ 88 ] and increased exposure of fatty acids [ 89 , 90 ] may disrupt the gut barrier function allowing translocation of LPS [ 91 , 92 ].

This results in moderately increased levels of LPS in the blood which is defined as metabolic endotoxemia [ 91 ], a condition linked to metabolic perturbations such as dyslipidemia, insulin resistance, NAFLD and cardiovascular disease [ 93 ].

LPS interacts with blood lipids in various ways. First, it increases the concentration of blood triglycerides by multiple mechanisms. In rats, low-dose LPS increases hepatic synthesis of VLDL, whereas high-dose LPS decreases lipoprotein catabolism [ 94 ].

Mice lacking the TLR4 co-receptor CD14 are resistant to hyperinsulinemia, insulin resistance and steatosis induced by a high-fat diet or LPS [ 91 ]. Second, plasma lipoproteins, in particular HDL, have the ability to neutralize the toxic effects of LPS [ 95 , 96 ]. The capacity of HDL to bind LPS may protect against inflammation.

This is supported by the observations that infusion of HDL prior to a LPS challenge reduced release of proinflammatory cytokines in humans [ 97 ] and that LPS induces higher levels of TNFα in hypolipidemic rats compared with controls [ 98 ].

LPS has been shown to promote atherosclerosis and cardiovascular disease. LPS-treated hypercholesterolemic rabbits have increased atherosclerosis compared with controls [ 99 ] and mice lacking TLR4 have reduced atherosclerosis and plaques with decreased amounts of lipid [ ].

In humans, high LPS levels during chronic infections are predictors of increased atherosclerotic risk [ ] and metabolic endotoxemia increases the risk for cardiovascular disease and mortality in patients with chronic kidney disease [ ].

Human TLR4 mutations have been shown to be associated with a decreased response to LPS [ ], reduced risk of carotid artery atherosclerosis [ ] and acute coronary events [ ]. Mouse studies have shown that hepatic steatosis is induced by a high-fat diet and associated with dysbiosis and increased intestinal permeability [ 91 ].

Moreover, chemically induced colitis in rats increases the levels of circulating LPS and worsens steatohepatitis during high-fat diet[ ].

Dysbiosis-induced permeability increases the levels of TLR ligands in the portal vein, thereby activating hepatic Kupffer cells and stellate cells to stimulate pro-inflammatory and pro-fibrotic pathways via inflammatory cytokines[ , ].

In addition, mucosal TLR activation appears to contribute to hepatic steatosis via the TLR adaptor MYD88 expressed in the intestine[ ]. Mice with an intestinal epithelial cell-specific deletion of MYD88 fed a high-fat diet have improved glucose homeostasis and decreased hepatic lipid content compared with wild-type mice[ ].

TLR signaling in the mucosa can also induce production of inflammasomes, multiprotein oligomers responsible for the activation of inflammatory responses. Inflammasomes activate a variety of pro-inflammatory and pro-fibrotic processes involved in the progression of liver disease[ ].

For example, activation of the NLRP3-inflammasome by LPS via TLR4 and TLR9 is involved in the development of fibrosis in NAFLD[ ]. Gut permeability has also been linked to NAFLD in humans. NAFLD patients have been shown to have increased gut permeability compared to healthy controls and gut permeability correlated with severity of steatosis but not with steatohepatitis in patients with NAFLD[ ].

Interestingly, patients with steatosis have also been shown to have a gut microbiota with increased genetic potential for biosynthesis of endotoxin[ 46 ]. The gut microbiota metabolizes methylamine-containing nutrients such as choline, lecithin and L-carnitine to generate trimethylamine TMA , which is further processed to trimethylamine N-oxide TMAO by flavin monooxygenases FMO in the liver.

TMAO levels have been correlated with risk of cardiovascular events[ ] and prevalence of cardiovascular disease[ , ].

Plasma TMAO levels in different mouse strains have been positively correlated with lesion size [ ] and transfer of microbiota from high- and low-TMAO-producing mice to atherosclerosis-prone Apoe knockout mice show that increased microbial capacity for TMA production increases aortic lesions[ ].

FMO3 is the primary enzyme converting TMA into TMAO. Knockdown of Fmo3 results in reduced atherosclerotic lesion areas, altered lipid and cholesterol metabolism, and decreased TMAO plasma levels [ , ]. FMO3 expression is regulated by bile acids by a mechanism that involves FXR [ ].

Gut microbiota processing of bile acids could therefore be an alternative mechanism by which the gut microbiota regulates TMAO production. The mechanisms by which TMAO contributes to atherosclerosis appears to be complex and not fully understood.

Antibiotic treatment reduces production of TMA and has been shown to suppress foam cell formation. TMAO can also contribute to atherosclerosis by inhibiting reverse cholesterol transport [ ] and by inducing atherosclerosis-promoting inflammatory proteins in vascular cells[ ].

In addition to atherosclerosis, increased levels of TMAO are also associated with a frequency of thrombotic events and platelet activation[ ]. Although many studies have reported associations between plasma levels of choline, TMAO, and cardiovascular disease [ , , , ] the role of TMAO in disease development is still under debate.

A recent study comparing conventional and GF Apoe knockout mice fed diets with or without choline supplementation found no effect of choline enrichment on aortic root atherosclerosis in mice[ ]. TMAO production was dependent on the presence of intestinal bacteria but no relationship between TMAO levels and lesions was observed.

These results are in contrast to Wang et al who found a significant correlation between TMAO and lesion size[ ]. Similarly, studies using diets supplemented with L-carnitine, which result in increased levels of TMAO, have shown opposite effects on aortic lesions in two different laboratories, further emphasizing context dependency on experimental outcome[ , ].

The gut microbiota has been targeted for treatment of diseases related to dyslipidemia. Strategies include supplementing the diet with fibers to enhance the growth or activity of beneficial bacteria prebiotics , live bacteria probiotics or a combination of pre- and probiotics symbiotics.

A meta-analysis of 11 minor clinical trials using fermented milk and probiotics show beneficial effects on serum lipid profiles[ ]. Another meta-analysis focusing on studies using Lactobacillus formulations found an improvement of total serum cholesterol and LDL, but not triglycerides or HDL[ ].

A recent meta-analysis of studies on treatment of NAFLD targeting the gut microbiota showed an overall reduction of AST and ALT levels when pooling data from 25 clinical trials using pre-, pro or symbiotics [ ]. Statins lower cholesterol levels by inhibiting HMG-CoA reductase, but may also exert a lipid-lowering effect through interaction with the gut microbiota.

Liu et al demonstrated that the cholesterol-lowering effect of rosuvastatin was reflected in microbial alpha diversity measured after eight weeks of treatment [ ].

Studies in mice have also shown that statins affect the gut microbiota [ , ]. The studies performed on microbiota-targeted therapy against dyslipidemia and NAFLD are heterogeneous, the cohorts small and the intervention periods short. Therefore, long-term benefits remain uncertain.

Prevention of atherosclerosis by modulation of the gut microbiota has not been studied in humans and data in mice are conflicting[ , , ]. An intricate crosstalk links the gut microbiota, dietary lipids and host lipid metabolism.

The microbiota processes lipids and other nutrient factors to produce metabolites with impacts on host lipid homeostasis and putative effects on pathophysiological processes. Studies in gnotobiotic and genetic mouse models have identified mechanisms behind these interactions, and studies in humans have found associations between microbial composition, lipid profiles and prevalence of metabolic diseases.

However, although it is evident that fat from different sources has different effects on the gut microbiota, the role of specific fatty acids is not known. It also remains to be investigated how the combination of lipids with other nutrients - such as dietary fibers — affects the gut microbiota.

Even though efforts have been made to understand how dietary pattern affect the gut microbiota[ , ], the importance of specific foods and combinations of nutrients in shaping microbial profile remains elusive. The association between diet, gut microbiota structure and dyslipidemia needs to be studied in large human cohorts to develop therapeutic strategies.

Given the individual differences in gut microbiota composition, it is likely that these strategies will require patient stratification and individual-based therapies. Sonnenburg JL, Backhed F.

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Effects of liraglutide on RCT and RCT-related protein expression in mice study. Furthermore, we investigated the effects of liraglutide on the proteins which were related to the process of RCT.

However, liraglutide treatment could significantly increase ABCA1 protein expression but no change was observed in the levels of ABCG1 and SR-B1 expression Fig. To investigate the mechanism of the effect of liraglutide on RCT in vivo, we carried out cell experiments.

Firstly, we observed the effects of different concentrations of glucose and liraglutide on the activity of HepG2 cells respectively. Data showed that high glucose could reduce the viability of HepG2 cells in a dose-dependent manner Fig.

The results also showed an increased intracellular fluorescence density in a dose-dependent manner Fig. Effects of different glucose a and liraglutide b concentrations on cell viability in HepG2 cells. Effects of different glucose concentrations on cholesterol efflux in HepG2 cells c.

Effect of Liraglutide nM on cholesterol efflux in HepG2 cells under high glucose condition d. Furthermore, the impact of liraglutide on the cell viability was examined. Data showed that liraglutide could significantly increase intracellular cholesterol efflux in HepG2 cells under high glucose condition Fig.

Furthermore, we observed liraglutide could increase both gene and protein expression of ABCA1 in HepG2 cells exposed to high glucose Fig. Effects of glucose at different concentrations 0, 5, 25, 50 mM on ABCA1, ABCG1 and SR-B1 gene a and protein b expressions in HepG2 cells.

Effects of liraglutide nM on ABCA1, ABCG1 and SR-B1 gene c and protein d expressions in HepG2 cells under high glucose HG, 50 mM condition. Under high glucose HG, 50 mM condition, U reduced the increased ABCA1 expression induced by liraglutide in HepG2 cells c.

Moreover, results also showed that liraglutide significantly reduced lipid deposition in the liver in vivo. In fact, DM is characterized by both glucose and lipid disorders. Evidence also support the notion that DM has higher rate of ASCVD and worse clinical outcomes due to the interaction of high glucose and dyslipidemia.

Meanwhile, serum lipid levels including TC, LDL-C and TG in diabetic mice fed with HFD were significantly higher than those fed with ND in diabetic mice and WT mice. More importantly, a marked inhibition of cholesterol efflux and the increased accumulation of lipid were also stably found, indicating that our model was suitable for further study regarding the impact of liraglutide on these pathophysiologic changes in the diabetic model.

As we know, liraglutide, a novel anti-diabetic medication, has recently become the first-line treatment for DM [ 33 , 34 , 35 ]. Previous studies have suggested that liraglutide exerts hypoglycemic effects by increasing insulin secretion, improving islet cell function, decreasing food intake, and reducing body weight [ 36 ].

In addition to down- regulation of the blood glucose, it also has the beneficial effects on the cardiovascular system [ 37 ].

A recent study showed that liraglutide had a cardiovascular protective effect in the type 2 diabetic patients presenting as a significant reduction of the cardiovascular events during a long-term follow-up [ 38 ]. Although the exact mechanism of this protective impact on cardiovascular system by liraglutide is currently not well determined, several animal and human observations have found that it may be associated with its reduction of body weight, recovery of liver lipid deposition, and reversal of hepatic steatosis [ 39 , 40 , 41 ].

Furthermore, the present study showed that liraglutide reduced the levels of TC, TG, and LDL-C in diabetic mice fed with HFD mediated by enhancing RCT.

It has been reported that RCT is a key process involving in the lipid metabolism and cardiovascular system protection. Hence, we hypothesized that the cardiovascular protective effects by liraglutide may be linked with RCT. That is the reason why we perform such study. Previous study has shown that GLP-1 may affect cholesterol homeostasis by regulating the expression of miR and ABCA1 in HepG2 cells [ 42 ].

In addition, GLP-1 treatment significantly increased the expression of ABCA1, ABCG1 and LXR-α, and improved cholesterol efflux from 3T3-L1 adipocytes [ 43 ]. In addition, several studies have indicated that liraglutide can induce body weight loss through reducing food intake, promoting satiety, and inducing autophagy [ 44 , 45 , 46 , 47 ].

At the same time, we also observed that liraglutide could modify TC and TG in diabetic mice, and improve hepatic lipid accumulation. Data indicated that the hepatoprotective effects of liraglutide appeared from its direct impact rather than its glucose lowering ability.

Several recent studies have also showed that liraglutide can alleviate non-diabetes steatohepatitis. Ipsen et al. found that liraglutide significantly decreased hepatic inflammation, liver injury and hepatocyte ballooning in advanced lean non-alcoholic steatohepatitis in guinea pigs induced by high-fat diet [ 48 ].

The study by Zhang et al. demonstrated that liraglutide had a protective effect on carbon tetrachloride CCl 4 -induced acute liver injury in mice, which significantly ameliorated the liver histopathological changes, reduced hepatocyte apoptosis, and enhanced mitochondrial respiratory functions [ 49 ].

Similarly, Milani et al. found that the hepatoprotective and therapeutic effects of liraglutide on acute liver injury in mice induced by CCl 4 might be attributable to a decrease in liver oxidative stress and the preservation of metabolism [ 50 ].

Therefore, it might be concluded that the potential hepatoprotective effect of liraglutide was beyond its glucose-lowering action. Gorgani-Firuzjaee et al.

showed that high glucose can induce de novo synthesis of cholesterol and VLDL production in HepG2 cells [ 52 ]. Pang et al. have found that long-term exposure of HepG2 cells to high glucose can induce reactive oxygen species ROS accumulation and DNA damage [ 53 ].

Do et al. have reported that high glucose can induce lipid accumulation in HepG2 cells [ 54 ]. It should be mentioned that signal transduction pathway regarding the role of liraglutide in regulating RCT is currently unclear although we found a beneficial impact of liraglutide on RCT in animal.

As described in the section of introduction, there are at least three key mediators ABCA1, ABCG1 and SR-B1 involving in RCT process. In order to explore which mediator is mainly associated with the RCT by liraglutide, we established a high glucose-stimulated HepG2 cell model.

By using this model, we confirmed the exact role of liraglutide in enhancing cell cholesterol efflux. We subsequently examined the effects of liraglutide on the expression of the mediators ABCA1, ABCG1 and SR-B1 and related signaling pathways.

Our findings may be an important complementary information concerning the relation of liraglutide to lipid metabolism. These results may widen our knowledge regarding the role of liraglutide in cardiovascular medicine beyond its glucose-lowering action.

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Transpl Proc. Article CAS Google Scholar. Rosenson RS, Brewer HB Jr, Davidson WS, et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Article PubMed PubMed Central Google Scholar. Phillips MC. Molecular mechanisms of cellular cholesterol efflux. J Biol Chem.

Article CAS PubMed PubMed Central Google Scholar. Wang X, Collins HL, Ranalletta M, et al. Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo.

J Clin Investig. Zhao SP, Wu ZH, Hong SC, et al. Effect of atorvastatin on SR-BI expression and HDL-induced cholesterol efflux in adipocytes of hypercholesterolemic rabbits. Clin Chim Acta. Marcel YL, Ouimet M, Wang MD. Regulation of cholesterol efflux from macrophages.

Curr Opin Lipidol. Duong M, Collins HL, Jin W, et al. Relative contributions of ABCA1 and SR-BI to cholesterol efflux to serum from fibroblasts and macrophages.

Arterioscler Thromb Vasc Biol. Rader DJ, Alexander ET, Weibel GL, et al. The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis. J Lipid Res. Bode B. An overview of the pharmacokinetics, efficacy and safety of liraglutide. Diabetes Res Clin Pract. Feher M, Vega-Hernandez G, Mocevic E, et al.

Effectiveness of Liraglutide and Lixisenatide in the Treatment of Type 2 Diabetes: Real-World Evidence from The Health Improvement Network THIN Database in the United Kingdom. Diabetes Ther.

Sposito AC, Berwanger O, Carvalho LS, et al. GLP-1RAs in type 2 diabetes: mechanisms that underlie cardiovascular effects and overview of cardiovascular outcome data. Tanaka A, Node K. Evidence-based and tailored medication in type 2 diabetes: a pathway learned from clinical trials.

Schisano B, Harte AL, Lois K, et al. GLP-1 analogue, Liraglutide protects human umbilical vein endothelial cells against high glucose induced endoplasmic reticulum stress. Regul Pept. Diaz-Soto G, de Luis DA, Conde-Vicente R, et al. Beneficial effects of liraglutide on adipocytokines, insulin sensitivity parameters and cardiovascular risk biomarkers in patients with Type 2 diabetes: a prospective study.

Davidson MH. Cardiovascular effects of glucagonlike peptide-1 agonists. Am J Cardiol. Chen XM, Zhang WQ, Tian Y, et al. Liraglutide suppresses non-esterified free fatty acids and soluble vascular cell adhesion molecule-1 compared with metformin in patients with recent-onset type 2 diabetes.

Cardiovascular diabetology. Alvarez CA, Lingvay I, Vuylsteke V, et al. Cardiovascular risk in diabetes mellitus: complication of the disease or of antihyperglycemic medications. Clin Pharmacol Ther. Masmiquel L. Cardiovascular effects and safety of glucose-lowering drugs: current situation.

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