And, estrogen induction of HMG-CoA reductase gene is dependent on the Red-ERE. The induction activity of estrogens occurs in the breast cancer cells but not in hepatic cells, indicating differential regulation of HMG-CoA reductase by estrogens in a tissue-specific manner [ 23 ].

Aromatase is an enzyme responsible for the key step in the biosynthesis of estrogens. Aromatase knockout ArKO mice display increased intra-abdominal adipose tissue and lipid droplet accumulation in the liver.

Total cholesterol and LDL are also elevated in these transgenes [ 24 ]. Supplement of estrogens in both ArKO mice and rats with ovariectomy OVX normalizes LDL and total cholesterol levels, confirming the important role of estrogens in the lipid homeostasis in both males and females [ 25 ].

Hormone replacement therapy HRT increases the expression of leucocyte ABCA1 gene, which mediates the efflux of cholesterol to the HDL particles, leading to the subsequent increase in the HDL cholesterol level [ 26 ].

Estrogens thus play an important role in the modulation of the total cholesterol level by reducing LDL and concurrently increasing HDL. The beneficial role of estrogens on cholesterol metabolism is mediated through nuclear and extranuclear ER-α and ER-β, as well as GPER.

Genetic deletion of ER-α in mice results in upregulation of the genes involved in hepatic lipid biosynthesis and downregulation of the genes involved in lipid transport, indicating that estrogens act via ER-α to regulate lipid metabolism [ 27 ].

Therefore, ER-α plays a more prominent role than ER-β. The roles of GPER in the regulation of metabolism are only beginning to emerge, which gains more attentions. GPER knockout mice exhibit impaired cholesterol homeostasis manifesting significantly a higher LDL level but a normal HDL level, suggesting that GPER mainly regulates LDL metabolism [ 29 ].

And, human individuals with a hypofunctional GPER P16L allele are associated with elevated plasma LDL. In vitro study shows that activation of GPER by the agonist upregulates hepatic LDLr expression [ 30 ]. The role of GPER signaling in cholesterol or metabolic control remains unclear and needs more further investigations [ 31 ].

In summary, estrogens protect against increases in the plasma cholesterol level mainly by activating ER-α and GPER. The human androgens include dehydroepiandrosterone, androstenedione, testosterone and dihydrotestosterone DHT. Testosterone can be converted to DHT via 5α-reductase. Testosterones and DHT are active androgens, because they are the only androgens capable of binding to androgen receptors ARs to exert biological functions.

AR is mainly expressed in the prostate, skeletal muscle, liver and central nervous system CNS. Like ERs, AR is a member of the steroid and nuclear receptor superfamily. The effect of androgen on cholesterol is still not conclusive. Clinical studies show that androgen deficiency, such as in old men, is associated with increased risks of dyslipidemia, higher serum cholesterol and LDL levels [ 32 ].

Another study has found that AR antagonists might be useful in the treatment of obesity in men [ 33 ]. In the animal studies, dihydrotestosterone DHT treatment in castrated obese mice decreases LDL secretion and increases the expression of hepatic scavenger receptor class B member 1 SR-1B which is important in regulating cholesterol uptake from HDL.

It also decreases the enzyme cholesterol 7α-hydroxylase which participates in bile formation and cholesterol removal. In another study using an orchidectomized Sprague—Dawley SD rat model, DHT treatment causes decreased lipid accumulation and cholesterol synthesis by increasing expression of carnitine palmitoyl transferase 1 and phosphorylation of HMG-CoA reductase via an AR-mediated pathway [ 34 ].

These contradictory results indicate a complex role of androgen on the cholesterol homeostasis in the liver. Growth hormone GH is secreted by the somatotroph cells of the anterior pituitary gland under neural, hormonal and metabolic control.

GH regulates postnatal growth, as well as lipid, glucose and energy metabolism. The molecular mechanism of GH action is relatively complicated. It affects metabolism through direct or indirect action via insulin-like growth factor-1 IGF-1 or antagonism of insulin action.

GH receptor GHR is a member of the cytokine receptor superfamily. Upon binding to GH, GHR activates the cytoplasmic tyrosine kinase Janus kinase 2 Jak2 and then recruits members of the signal transducer and activator of transcription STAT family of transcription factors.

Phosphorylated STATs translocate into the nucleus and modulate the transcription of multiple target genes, including IGF-1, ALS and suppressor of cytokine signaling SOCS [ 36 ].

There exists a negative relationship between obesity and GH. Enormous evidence supports that GH alters lipid metabolism. Clinical studies have shown a significant association between lower serum GH levels and non-alcoholic fatty liver disease NAFLD. Hypopituitary patients with GH deficiency are more prone to NAFLD than control subjects [ 37 , 38 , 39 ].

GH supplementation has been shown to improve the NAFLD and the metabolic dysfunction [ 40 , 41 ]. In rodent studies, high-fat diet feeding and obesity suppress pulsatile GH secretion [ 42 ].

In turn, chronic GH treatment ameliorates hepatic lipid peroxidation and improves lipid metabolism in high-fat diet-fed rats [ 43 ]. Hypophysectomy is a surgery process in which the pituitary gland hypophysis is removed, leading to an impairment of GH secretion.

This model is used for investigating the GH function in animals under pathophysiology conditions. Increase of hepatic LDLr and hypocholesterolemia induced by estrogens is completely attenuated in hypophysectomized rats. Only GH supplementation is able to restore this effect of hypophysectomy.

This study indicates that GH secretion is critical for the control of plasma LDL levels in humans [ 44 ]. GH is also important for the synthesis of bile acids by maintaining the normal activity of cholesterol 7α-hydroxylase. Hypophysectomized rats show significantly reduced activities of HMG-CoA reductase and cholesterol 7α-hydroxylase and hence an inhibition of cholesterol and bile acid biosynthesis.

GH substitution restores the enzymatic activity of 7α-hydroxylase and increases the fecal excretion of bile acids [ 45 ]. Treatment of LDLr-deficient mice with GH reduces their elevated plasma cholesterol and triglyceride levels by stimulating the activities of HMG-CoA reductase and cholesterol 7α-hydroxylase [ 46 ].

GH thus regulates plasma lipoprotein levels and bile acid metabolism by altering hepatic LDLr expression and the enzymatic activity of cholesterol 7α-hydroxylase, respectively. GHR is present in the liver and critical for the hepatic lipid metabolism.

Laron dwarfism is a disorder characterized by an insensitivity to GH due to a genetic mutation of GHR. These male patients manifest NAFLD in adults [ 47 ].

Liver-specific deletion of GHR in mice leads to increased circulating free fatty acids and fatty liver as a result of increased synthesis and decreased efflux of triglyceride [ 48 ]. Binding of GH to GHR activates JAK2-STAT5 signaling pathway and modulates a number of target genes.

All these findings suggest that hepatic GH signaling is essential for the regulation of intrahepatic lipid and cholesterol metabolism.

Glucagon is a aa peptide hormone secreted from the pancreatic islet alpha cells in response to low glucose. It is a well-known counter-regulatory hormone to insulin, mainly stimulating hepatic glucose production by increasing glycogenolysis and gluconeogenesis and concurrently inhibiting glycogen synthesis.

Glucagon also affects hepatic cholesterol metabolism. The relationship between glucagon and cholesterol has been investigated since the s [ 51 ].

The portacaval shunt surgery in a 6-year-old girl with the homozygous form of familial hypercholesterolemia disorder has been reported to significantly reduce LDL and cholesterol synthesis 5 months after surgery.

This alteration is associated with a marked elevation of bile acids and the glucagon level, indicating that glucagon may improve hepatic lipid metabolism [ 52 ]. In the animal study, infusion of glucagon into the hyperlipidemic rat reduces circulating VLDL apoprotein and serum TG levels.

It is due to the inhibition of incorporating amino acid into the apoprotein by glucagon [ 53 ]. Chronic glucagon administration in rats significantly reduces serum cholesterol and triglyceride levels but not in the liver.

The internal secretion of cholesterol and cholesterol transformation into bile acids measured by an isotope balance method are strikingly increased, suggesting that glucagon stimulates cholesterol turnover rate [ 54 ].

Studies by Rudling et al. Moreover, the induction of LDLr by glucagon is not due to increased mRNA levels, indicating a novel posttranscriptional regulatory mechanism present in the liver [ 55 ].

In humans, glucagon administration represses cholesterol 7α-hydroxylase CYP7A1 mRNA expression by increasing the PKA phosphorylation of HNF4a and reducing its ability to bind with the CYP7A1 gene, thus inhibiting bile acid synthesis [ 56 ].

Glucagon receptor, encoded by the GCGR gene, is a seven-transmembrane protein and belongs to the class II guanine nucleotide-binding protein G protein -coupled receptor superfamily.

They are abundantly expressed in the liver and kidney. In the liver, glucagon receptors are mainly located in hepatocytes, with a small number expressed on the surface of Kupffer cells [ 57 ].

Several glucagon receptor antagonists GRA have been developed to reduce hepatic glucose overproduction and improve the overall glycemic status. However, some GRAs including MK have been shown to dose-dependently increase LDL in T2DM patients.

In the rodent preclinical trial, blockade of glucagon receptor using various GRAs elevates plasma LDL-c and total cholesterol. This is caused by increased cholesterol absorption instead of the change in cholesterol synthesis or secretion [ 60 ].

Taken together, these results suggest that glucagon plays a hypolipidemic effect through its glucagon receptors, making it an interesting and attractive pharmaceutical agent for the treatment of dyslipidemia and obesity.

Irisin is a newly identified hormone encoded by the gene fibronectin type III domain-containing protein 5 FNDC5.

It is secreted into the circulation as a cleaved protein product and induced by exercise [ 61 ]. Irisin is proposed to mediate the metabolic benefits of exercising by promoting the browning of subcutaneous adipose tissue, reducing visceral obesity and improving glucose and cholesterol metabolism.

Circulating the irisin level is negatively associated with fat mass, fasting glucose and dyslipidemia, as well as intrahepatic TG contents in humans [ 62 , 63 ]. A higher baseline irisin level is associated with the metabolic benefits of diet-restricted treatment on human weight loss [ 64 ].

Lentivirus-mediated FNDC5 overexpression or subcutaneous perfusion of irisin promotes lipolysis and reduces hyperlipidemia in obese mice [ 65 ]. Irisin is negatively associated with HDL cholesterol and large HDL particles in adults with higher cardiovascular risk [ 66 ].

In addition, the serum irisin level is significantly higher in the NAFLD patients than in normal subjects [ 67 ]. Elevation of saliva irisin is positively related to total cholesterol [ 68 ]. Subcutaneous infusion of irisin decreases body weight, plasma total, VLDL, LDL, HDL cholesterol in diet-induced obese mice.

The hepatic levels of total and esterified cholesterol are also reduced. These alterations are associated with significant reduction in the expression of the genes important for cholesterol synthesis, including Srebp2 , HMG-CoA reductase Hmgcr , the liver X receptor α Lxrα , Nr1h3 and HMG CoA synthase Hmgcs in the liver and primary hepatocytes.

Further experiments demonstrate that irisin inhibits cholesterol synthesis in hepatocytes through the activation of AMPK and SREBP2 [ 69 ]. As a novel hormone, evidence supporting the critical role of irisin in the regulation of cholesterol or lipid metabolism is still limited.

Cholesterol balance is regulated at multiple steps, including the biosynthesis, uptake, intracellular transport and conversion to bile acids for excretion. Hormones affect cholesterol biosynthesis and uptake by altering the transcription of genes critical for these biological processes Table 1. Novel identified hormones are constantly added into the list implicated in cholesterol balance process.

This work was supported by the National Natural Science Foundation of China , Natural Science Foundation of Guangdong Province A , Shenzhen Science and Technology Project JCYJ, JCYJ , Shenzhen Peacock Plan KQTD,— and Natural Science Foundation of SZU Licensee IntechOpen.

This chapter is distributed under the terms of the Creative Commons Attribution 3. Edited by Madan L. Open access peer-reviewed chapter Hormonal Regulation of Cholesterol Homeostasis Written By Zhuo Mao, Jinghui Li and Weizhen Zhang. DOWNLOAD FOR FREE Share Cite Cite this chapter There are two ways to cite this chapter:.

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IntechOpen Cholesterol Good, Bad and the Heart Edited by Madan L. From the Edited Volume Cholesterol - Good, Bad and the Heart Edited by Madan L. Nagpal Book Details Order Print.

Chapter metrics overview 1, Chapter Downloads View Full Metrics. Impact of this chapter. Abstract Cholesterol homeostasis is tightly regulated by a group of endocrine hormones under physiological conditions.

Keywords cholesterol thyroid hormone sex hormones growth hormone glucagon and irisin. Introduction Cholesterol is mainly composed of low-density lipoprotein LDL , very-low-density lipoprotein VLDL and high-density lipoprotein HDL. Thyroid hormone and thyroid hormone receptors Thyroid hormones THs include thyroxine T4 and triiodothyronine T3.

Role of TH in cholesterol metabolism There is substantial evidence linking TH status with cholesterol or lipid metabolism.

Interaction with other transcription factors In addition to the direct action on the cholesterol-related genes, TRs also cross talk with many nuclear receptors to regulate their transcriptions. Estrogen and estrogen receptors The predominant and most important biologically relevant form of estrogen is 17β-estradiol E2.

Role of estrogens in cholesterol homeostasis The influence and mechanism of estrogens on cholesterol metabolism have been investigated for a long time. Androgens The human androgens include dehydroepiandrosterone, androstenedione, testosterone and dihydrotestosterone DHT.

Growth hormone and growth hormone receptors Growth hormone GH is secreted by the somatotroph cells of the anterior pituitary gland under neural, hormonal and metabolic control. Role of GH in cholesterol and lipid metabolism There exists a negative relationship between obesity and GH.

Table 1. Effect of hormones on cholesterol metabolism. References 1. Sinha RA, Singh BK, Yen PM. Thyroid hormone regulation of hepatic lipid and carbohydrate metabolism. Trends in Endocrinology and Metabolism. Schwartz HL et al. Quantitation of rat tissue thyroid hormone binding receptor isoforms by immunoprecipitation of nuclear triiodothyronine binding capacity.

The Journal of Biological Chemistry. Sterols and stanols are substances found in plants that help block the absorption of cholesterol. Foods that have been fortified with sterols or stanols are available. Margarines and orange juice with added plant sterols can help lower LDL cholesterol.

It's not clear whether food with plant sterols or stanols lowers your risk of heart attack or stroke — although experts assume that foods that lower cholesterol do cut the risk. Plant sterols or stanols don't appear to affect levels of triglycerides or of high-density lipoprotein HDL cholesterol, the "good" cholesterol.

Whey protein, which is found in dairy products, may account for many of the health benefits attributed to dairy. Studies have shown that whey protein given as a supplement lowers both LDL and total cholesterol as well as blood pressure.

You can find whey protein powders in health food stores and some grocery stores. Getting the full benefit of these foods requires other changes to your diet and lifestyle. One of the most helpful changes is limiting the saturated and trans fats you eat.

Saturated fats — such as those in meat, butter, cheese and other full-fat dairy products — raise your total cholesterol. Trans fats, sometimes listed on food labels as "partially hydrogenated vegetable oil," are often used in margarines and store-bought cookies, crackers and cakes.

Trans fats raise overall cholesterol levels. The Food and Drug Administration banned the use of partially hydrogenated vegetable oils in processed foods sold after January 1, There is a problem with information submitted for this request.

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Request Appointment. Cholesterol: Top foods to improve your numbers. Products and services. Cholesterol: Top foods to improve your numbers Diet can play an important role in lowering your cholesterol.

By Mayo Clinic Staff. Thank you for subscribing! Sorry something went wrong with your subscription Please, try again in a couple of minutes Retry. Show references Tangney CC, et al. Lipid management with diet or dietary supplements. Accessed March 6, Your guide to lowering your cholesterol with therapeutic lifestyle changes.

National Heart, Lung, and Blood Institute. Accessed March 8, Grundy SM, et al. Journal of the American College of Cardiology.

Prevention and treatment of high cholesterol hyperlipidemia. American Heart Association. Feather A, et al. Lipid and metabolic disorders. Elsevier; Pacheo LS, et al. Avocado consumption and risk of cardiovascular disease in US adults.

The study also found that in mice, a subset of bacteria called Bacteroides help to regulate cholesterol levels in the blood. Promoting Bacteroides early in life has implications for proper development in infants and lifelong health. The findings could lead to new therapies that replace the multibillion-dollar cholesterol-lowering drug industry.

Potential treatments could include targeted diets, probiotics or new drugs derived from the molecules these bacteria produce, all of which could reduce the host of side effects that come with current drugs. Although cholesterol sulfate is readily produced in human tissues, this study is the first to show that the gut microbiome can also produce cholesterol sulfate.

They found that Bacteroides were producing cholesterol sulfate. Further, the researchers used germ-free mice inoculated with engineered Bacteroides that lacked an enzyme needed to convert cholesterol to cholesterol sulfate. The experiment revealed that these mouse gut microbiomes could not make cholesterol sulfate, while the microbiomes in germ-free mice colonized with normal Bacteroides produced it.

While most cholesterol is made by the liver, about one-fifth comes from animal foods.

non-interacting microbes blue. The study is one of the first to identify species of gut bacteria that convert cholesterol from animal foods into a molecule called cholesterol sulfate.

Though more study is needed, early clues reveal cholesterol sulfate acts as a signaling molecule for a slew of biological pathways, including those involved in infant health and development, regulating immune cells and digestion.

The study also found that in mice, a subset of bacteria called Bacteroides help to regulate cholesterol levels in the blood.

Promoting Bacteroides early in life has implications for proper development in infants and lifelong health. The findings could lead to new therapies that replace the multibillion-dollar cholesterol-lowering drug industry. Potential treatments could include targeted diets, probiotics or new drugs derived from the molecules these bacteria produce, all of which could reduce the host of side effects that come with current drugs.

Although cholesterol sulfate is readily produced in human tissues, this study is the first to show that the gut microbiome can also produce cholesterol sulfate.

They found that Bacteroides were producing cholesterol sulfate. Further, the researchers used germ-free mice inoculated with engineered Bacteroides that lacked an enzyme needed to convert cholesterol to cholesterol sulfate.

The experiment revealed that these mouse gut microbiomes could not make cholesterol sulfate, while the microbiomes in germ-free mice colonized with normal Bacteroides produced it.

While most cholesterol is made by the liver, about one-fifth comes from animal foods. The findings have important implications for the importance of breast milk for providing proper nutrition, and for further study of baby formulas that lack cholesterol, such as soy-based products, and whether they deprive infants of necessary nutrients.

RNF also contains a YIYF sequence in the SSD, which is essential for its binding with Insigs, and in the RING finger domain, the Cys residue is responsible for RNF activity Jiang et al. Why multiple E3 ubiquitin ligases are involved in HMGCR degradation and which ligases are responsible for HMGCR ubiquitination under certain conditions need further investigation.

In contrast to ubiquitination, HMGCR is deubiquitinated by mTORC1-phosphorylated USP20, which preferentially hydrolyzes K48 and K63 linkages, and stabilized HMGCR increases cholesterol synthesis in the feeding state Lu et al. The extracted HMGCR is transferred to the cytosol from the ER membrane by the 19S regulatory subunit of the proteasome.

Subsequently, it is delivered to the proteolytic core of the 20S proteasome for degradation. The extraction process is enhanced by geranylgeraniol, which is a derivative of isoprenoid geranylgeranyl pyrophosphate GGpp.

In the presence of a substrate of GGpp, UBIAD1, which binds with HMGCR and blocks its membrane extraction, is transported to the Golgi and removes the inhibition of HMGCR degradation. UBIAD1 is a membrane prenyltransferase that can catalyze the transfer of isoprenyl groups to aromatic acceptors and produce ubiquinones, hemes, chlorophylls, vitamin E, and vitamin K.

UBIAD1 knockout in mice is embryonic lethal, and the phenotype can be rescued by knocking in HMGCR, which is a resistant mutant Schumacher et al. Therefore, HMGCR levels can be regulated with nonsterol mevalonate pathway products. Another posttranslational regulation of HMGCR is phosphorylation.

The Ser residue in the C-terminal catalytic domain of HMGCR is phosphorylated by AMPK, and phosphorylation at Ser disrupts HMGCR activity and restricts the flux of the mevalonate pathway rapidly but does not affect sterol-induced ubiquitination and subsequent degradation Clarke and Hardie, SM catalyzes the first oxygenation step in cholesterol synthesis; it introduces an epoxide group to squalene, converts alkene squalene into squalene epoxide, and is proposed to be a rate-limiting step in cholesterol synthesis.

There are three SREs in the SM promoter: two adjacent SREs near the initiation site that partially respond to sterol via SREBP2 and a third SRE that is sterol independent. Other transcriptional cofactors and factors, including NF-Y, Sp1, YY1, c-Myc, and IRF-1, participate in the regulation of SM transcription Chua et al.

Mirb is reported to promote SM mRNA degradation Qin et al. The focus of SM regulation, similar to that of HMGCR, is posttranslational. SM can be ubiquitinated and degraded under cholesterol abundance. The phenomenon of cholesterol-induced squalene accumulation suggests that SM, similar to HMGCR, is another flux-controlling enzyme Gill et al.

The N-terminal residues of SM contain a cholesterol-sensitive amphipathic helix and a reentrant loop; the amphipathic helix binds membranes with absent cholesterol, the affinity is reduced upon cholesterol addition, and the released helix forms a disordered sequence Chua et al.

MARCH6, an E3 ligase that physically interacts with conformationally changed SM Zelcer et al. In contrast to cholesterol-induced SM degradation, the accumulated substrate squalene binds to the N-terminal residues of SM, altering the recognition of MARCH6, and stabilizing SM on the ER membrane Yoshioka et al.

In addition to ubiquitination, MARCH6 can regulate SREBP2 at the transcriptional level; thus, HMGCR and SM are controlled. During ERAD, SM is truncated by N-terminal degradation, which results in defects in sterol sensing. Truncated SM has similar abundance and is constitutively active. The distinction of SM and truncated SM function needs further investigation in detail.

Cholesterol is distributed unevenly in cellular membranes. The ER, mitochondria, and lysosomes are characterized by small amounts of cholesterol Maxfield and Wüstner, To achieve compositional heterogeneity, cholesterol needs to be transported in cells in a dedicated manner.

The synthesized cholesterol in the ER is transported to organelles immediately, and this cholesterol transport is primarily coupled with the transport and metabolism of phosphoinositide, phosphatidylserine PtdSer , and sphingolipids Holthuis and Menon, Cholesterol trafficking is mediated by vesicular and nonvesicular trafficking systems Prinz, ; Luo et al.

Vesicular transport plays an important role in the response to trafficking of proteins in extracellular and endocytic pathways, and along with protein transport, cholesterol can traffic between organelles in the secretory pathway continuously Holthuis and Menon, However, a number of lines of evidence support that there is an alternative nonvesicular transport response for rapid and bulk cholesterol exchanges in the secretory pathway that do not receive vesicular trafficking.

The nonvesicular transport system includes cholesterol traveling spontaneously between membranes at a low rate of desorption and movement, horizontal movement in continuous membranes, and movement in two leaflets of the membranes.

In vitro investigations have demonstrated that the spontaneous exchange of cholesterol is related to aqueous-phase solubility and membrane curvature.

Cholesterol exchanges rapidly from donors of small vesicles that have higher membrane curvature than large vesicles Lev, However, cholesterol interacts with sphingolipid and GPI-anchored proteins to form condensed complexes in the bilayer, and the nanostructure decreases the desorption of cholesterol from membranes.

Lipid transfer proteins LTPs have been identified to accelerate the transport of lipids, including cholesterol Wong et al. Many LTPs are localized to MCSs and undergo conformational changes from open bridges to closed tubes to facilitate the transfer of lipids Figure 3.

To date, at least 27 protein families have been found in lipid trafficking. FIGURE 3. Major molecules in intracellular cholesterol transport. Between the ER and the TGN, OSBP bridges the two membranes, sterols of the ER that bind to the ORD are transferred to the TGN, and the ORD of OSBP transfers PI 4 P of the TGN back to the ER.

The conserved mammalian ortholog of Lam6p is GRAMD1A, which is proposed to interact with the receptor of the mitochondria to transfer sterols.

Most newly synthesized cholesterol is transported to the trans-Golgi network TGN , which is a sorting site for lipids, to maintain a low concentration in the ER.

Oxysterol-binding protein OSBP , a bridge between the ER and Golgi membranes, and has been observed to mediate cholesterol transfer. OSBP contains three conserved domains: the N-terminal pH domain, the central FFAT motif, and the C-terminal OSBP-related domain ORD , which recognize PI 4 P and small GTPase ADP-ribosylation factor Arf1 in the Golgi, target the VAP-A protein in the ER, and bind sterols, respectively.

The architecture of OSBP supports cholesterol export Antonny et al. In detail, first, the membranes are tethered between Golgi and ER by the pH domain and FFAT motif of OSBP; second, sterols that bind to the ORD are transferred to the Golgi; third, at the Golgi, the ORD of OSBP transfers PI 4 P, which is synthesized by phosphatidylinositol 4-kinase PI4K IIIβ, back to the ER; and fourth, PI 4 P is dephosphorylated to PI via Sac1, which is an ER-localized phosphatase.

The low ratio of PI 4 P to sterols in the ER makes the phosphorylation and dephosphorylation cycle move continuously to fuel cholesterol export.

The exchange between cholesterol in the ER and PI 4 P in the Golgi is maintained by PI4KIIIβ and Sac1 Antonny et al. Intriguingly, Sac1 also acts in trans on 4-phosphatase on PI 4 P in a manner mediated by FAPP1 when the concentration of PI 4 P is elevated in the TGN Venditti et al.

The two modes of Sac1 activity may coexist in cells such that when the concentration of PI 4 P reaches a threshold, the trans-phosphatase activity of Sac1 is enhanced and coordinated with the in cis phosphatase activity to lower PI 4 P levels in the TGN.

Moreover, the in cis activity of Sac1 is required for contact sites between the PM and the ER or the late endosomes LEs and the ER Del Bel and Brill, A recent study found that in cholesterol-fed cells, the ER-anchored cholesterol escort SCAP interacts with the VAP-OSBP complex via Sac1.

Deletion of SCAP inhibits PI 4 P transport and carriers of the Golgi network to the cell surface CARTS Wakana et al. Whether cholesterol perturbation causes disruption of the cycle between PI 4 P and cholesterol is unclear. Mitochondria are important organelles in cells that can synthesize phosphatidylglycerol, cardiolipin, and phosphatidylethanolamine but must import phosphatidylcholine, phosphatidylinositol, PtdSer, and sterols from other organelles to maintain normal function Flis and Daum, ; Horvath and Daum, The ER and mitochondria are physically connected at the mitochondria-associated membrane MAM.

Most cholesterol transfer from the ER to mitochondria takes place on the MCSs of MAMs Giordano, There are three families of LTPs conserved in yeast and mammals as tethers, lipid sensors, or transporters at the MCSs between the ER and mitochondria.

The first is the ORP family; specifically, ORP5 and ORP8 interact with tyrosine phosphatase-interacting protein 51 PTPIP51 at the MCSs and mediate ER-mitochondrial contact as well as at the PM-ER to facilitate sterol transport in mammalian cells Chung et al.

The second is the START family, which is responsible for cholesterol transport from the OMM to the IMM under hormonal stimulation, after which the cholesterol in the IMM is transformed into pregnenolone for production of steroids or bile acid in hepatic cells Elustondo et al.

The third is the LAM-GRAM family, which was recently discovered in yeast and includes Lam6 and Lct1, which are ER-anchored proteins located in the ER-mitochondria MCSs that bind with the mitochondrial import receptors Tom70 and Tom71 in yeast Murley et al.

The conserved orthologs in mammals are GRAMD1A and GRAMD1C, which are involved in lipid transfer in the PM Naito et al. Thus, we know little about cholesterol transfer at the ER-mitochondria MCSs in mammals at present.

The discovery of new sterol transfer molecules will further illustrate the important roles of cholesterol and MCSs in mitochondria. Endosomes also have abundant contact sites with the ER, and cholesterol is transferred from the ER to late endosomes LEs and lysosomes LYs via MCSs in cells.

StAR-related lipid transfer protein 3 STARD3 , also known as MLN64, contains a conserved FFAT-like motif that interacts with VAPs in the ER membrane, mediates MCS formation between the ER and LE and transfers newly synthesized cholesterol from the ER to endosomes via a sterol-binding domain Wilhelm et al.

Similar to another sterol transfer protein, ORP1L, which responds to cholesterol transfer from endosomes to the ER, STARD3 binds VAP to form a tether between the ER and endosome Ridgway and Zhao, Whether these proteins compete with each other for VAP binding and how the major molecule that binds with VAP is regulated needs further investigation.

Cholesteryl esters CEs carried by low-density lipoprotein LDL are absorbed by LDL receptors LDLRs at the membrane and hydrolyzed by acid lipase in LEs. The released free cholesterol is transferred to other organelles: ER, PM, mitochondria, TGN, and peroxisomes.

Additionally, ORP5 is responsible for the cycling of PS in the ER and PI 4 P in the PM to maintain the low level of PI 4,5 P2 in the PM Ghai et al.

Peroxisomes, as sites of lipid metabolism, play an important role in the cholesterol trafficking pathway. Synaptotagmin VII Syt7 of lysosomes and PI 4, 5 P2 of peroxisomes is located at MCSs that form between the two organelles. Either Syt7 or PI 4, 5 P2 is essential to the formation of the MCSs and to cholesterol export from LYs Chu et al.

Syt7 has been reported to be a potential oncogenic target and to be involved in synaptic transmission as a calcium sensor Turecek et al. Thus, further side effects need to be studied intensively when targeting Syt7 to cure disease.

Cholesterol is an essential lipid that serves as a precursor of steroid hormones, bile acids, and oxysterols in special mammalian tissues.

Disturbed cholesterol homeostasis in humans is related to cardiovascular disease, cancer, neurodegenerative disease, and congenital disease. Thus, the de novo synthesis of cholesterol in cells and regulation, coordination between intracellular syntheses, import of exogenous cholesterol, biological distribution in organelles, transport of cholesterol in and out of cells, trafficking of intracellular cholesterol, and how to coordinate all the above processes precisely need to be researched continuously.

Because of the central role of SREBP2 in cholesterol homeostasis, numerous dysregulations of the gene in certain disease phenotypes are connected to cholesterol homeostasis. Some investigations have revealed that SREBP2 can function independently in addition to regulating cholesterol synthesis.

For example, in circulating melanoma cells, SREBP2 contributes to ferroptosis resistance by inducing transcription of the ion carrier transferrin TF Hong et al. Therefore, SREBP2, as a transcription factor, not only plays a key role in cholesterol homeostasis but also exerts multifunctional effects in pathophysiology.

The additional functions and related mechanisms need further investigation. The newly synthesized cholesterol and the released free cholesterol hydrolyzed from endocytosis LDL-C need to be distributed rapidly to maintain the normal functions of cells.

Although more LTPs are identified and closely connect with MCSs in membranes, the detailed mechanisms by which they facilitate cholesterol transfer, and whether they have other pathophysiological roles and can be inhibited as drug targets, are still not well known.

For example, the well-known function of STARD3 is to tether the ER and endosome and facilitate cholesterol transfer from the ER to the endosome. Recent findings indicate that high STARD3 levels are associated with worse overall survival OS , relapse-free survival RFS , and disease metastasis-free survival MFS.

Thus, STARD1 could be a preclinical marker of AD at early stages. In alcoholic liver disease ALD , STARD1 not only acts as a sterol transporter but also serves as a UPR and ER stress gene, which is stimulated by alcohol and facilitates ALD development Marí et al.

Moreover, STARD1 is expressed in many extra-adrenal and extra-gonadal organs, cells, and malignancies, including brain, eye, liver, vasculature, macrophages, heart, lung, skin cells, and so on.

In addition, in macrophages, STARD1 also facilitated the cholesterol efflux by activate LXRs Taylor et al.

The functions of STARD1 in extra-endocrine tissues need more attention in future research. The functional ORD of ORP5 interacts with mTOR1 and participates in cancer cell invasion and tumor progression. ORP5 depletion impairs mTOR localization to lysosomes, abolishes mTORC1 activity, and inhibits cell proliferation in HeLa cells Du et al.

The oncogenic gene KRAS is anchored on PM to maintain biological activity. The C-terminal of KRAS binds with specificity to PtdSer in the PM. Both ORP5 and ORP8 are responsible for exchanging PtdSer in the ER and phosphatidylphosphate in the PM.

Depletion of ORP5 or ORP8 reduces PtdSer in the PM, causes KRAS mislocalization in vitro , and attenuates KRAS signaling in vivo ; in addition, it reduces cell proliferation of KRAS-dependent cancer cells Kattan et al. GRAMD1A, which facilitates lipid transfer between the mitochondria and the ER, similar to ORP5, promotes HCC self-renewal, tumor growth, and resistance to chemotherapy.

The effects of GRAMD1A are mediated by STAT5 Fu et al. In addition, during autophagosome biogenesis, GRAMD1A is bound by autogramins on its StART domain, causing accumulation of GRAMD1A at the sites of autophagosome initiation Laraia et al.

As indicated for the above-mentioned molecules, although alterations in both cholesterol and its related genes are observed in certain pathological conditions simultaneously, the exact functions of the molecules aside from cholesterol regulation need to be further investigated.

The most extensive application of lipid-lowering drugs in the clinic is antiatherogenic to reduce the morbidity and mortality of cardiovascular disease. Aside from cardiovascular disease, increasing evidence indicates that dysregulation of cholesterol homeostasis or some related genes correlates with cancers Kopecka et al.

For example, cholesterol- and lipid-mediated innate immune memory induces COVIDrelated cytokine storms Sohrabi et al. In AD, AD brains retain significantly more cholesterol than age-matched nondementia control ND brains; the APP acts as a lipid-sensing peptide on cholesterol and forms MAMs in the ER, causing extracellular cholesterol internalization in the ER Montesinos et al.

In addition to the antiatherogenic drugs approved by the Food and Drug Administration FDA , several molecules in the mevalonate pathway have emerged as promising drug targets for cancer and AD.

For example, SC4MOL and NSDHL inactivation sensitizes tumor cells to EGFR inhibitors Sukhanova et al. Therefore, further genetic screening of drug targets in the mevalonate pathway and cholesterol homeostasis for cancers and neurodegenerative disease therapy or prevention are essential.

Targeting the mevalonate pathway or cholesterol homeostasis combined with medicine used in the clinic may benefit disease therapy. In recent years, additional traditional Chinese medicines have been observed to have cholesterol-lowering effects, including aloe-emodin Su et al.

The mechanisms of some of these medicines involve SREBP2 transcription and maturation processes. Therefore, it is worth testing additional traditional Chinese medicines based on the present medicinal knowledge.

Along with the increasing understanding of cholesterol homeostasis, more regulator molecules have been identified to be involved in pathological conditions. Targeting of related molecules has been demonstrated to ameliorate certain symptoms; however, more research is needed to assess the side effects.

Aside from cholesterol itself, intermediates of the mevalonate pathway, lipid transfer proteins, and metabolites of cholesterol all warrant further research. QS and JC wrote the manuscript. XZ drew the Figures and edited the review. XT provided thoughts and corrected the review.

All authors contributed to the article and approved the submitted manuscript. 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.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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