Regulation Of Hepatic Cholesterol Metabolism Research Articles

The Effects of High Hydrostatic Pressure Extract of Mulberry Fruit on Hepatic Cholesterol Metabolism in Rats (P06-013-19)

ObjectivesThe objective of this study is to investigate the effects of high hydrostatic pressure (HHP) extract of mulberry fruit on the regulation of hepatic cholesterol metabolism in high-cholesterol diet fed rats. MethodsMale Sprague-Dawley rats(6-week-old) were randomly divided into 5 groups, and fed with a normal diet (NOR), High cholesterol diet (HC), HC supplemented with 0.4% mulberry (ML) or 0.8% mulberry (MH) and HC treated with statin (ST) for 4 weeks. ResultsThe HHP extract of mulberry fruit did not affect body weight gain and food intake and reduced the serum and liver lipids in the mulberry supplemented groups (ML, MH). In this study, we found that the HHP extract of mulberry fruit changed the level of genes involved in hepatic cholesterol metabolism. In the MH group, the mRNA levels of apolipoprotein A-1 (apoA-1), ATP-binding cassette transporter A1 (ABCA1) and lecithin-cholesterol acyltransferase (LCAT), which are involved in hepatic HDL biogenesis, were significantly increased by 1.80-, 1.77- and 2.65-fold, respectively, compared with the HC group. The MH group also significantly upregulated mRNA levels of cholesterol efflux related gene such as the liver X receptor α (LXRα), ATP-binding cassette protein G5 (ABCG5) and ATP-binding cassette protein G8 (ABCG8) compared to the HC group in the liver tissue. ABCG5 and ABCG8 expression levels of the MH group were also higher than those of the ST group. The mRNA level of cholesterol 7a-hydroxylase (CYP7A1), which is bile acid synthetic rate-limiting enzyme was higher in the MH group than that of the HC group. Furthermore, the immunohistochemical staining intensity became evident for CYP7A1 in liver of the MH group. ConclusionsThese results suggest at least partial involvement of HDL cholesterol synthesis, cholesterol efflux and bile acid synthesis in HHP extract of mulberry fruit mediated beneficial effects on hepatic cholesterol metabolism. Funding SourcesNone.

Abstract P293: Effects of Diets That Vary in Fatty Acid Composition on Fecal Short-chain Fatty Acid Levels and Their Relationship With Circulating Lipids and Lipoproteins

Introduction: The short-chain fatty acids (SCFA) acetic acid, propionic acid, and butyric acid are microbial-produced metabolites that can influence host physiology through regulation of hepatic cholesterol metabolism. These biologically relevant gut metabolites may play a role in the hypocholesterolemic effects of select dietary components. The objective of this exploratory study was to determine the effects of diets that differ only in fatty acid composition on fecal SCFA levels and to assess their correlations with circulating lipids, lipoproteins, and apolipoproteins. Hypothesis: We assessed the hypothesis that dietary fat quality will differentially affect fecal SCFA and there will be significant associations between fecal SCFA levels and those of circulating total cholesterol, low-density lipoprotein-cholesterol (LDL-C), non-high-density lipoprotein-cholesterol (non-HDL-C), and apolipoprotein (apo) B. Methods: In a double-blind, randomized, three period crossover, controlled feeding clinical trial, participants with ≥2 metabolic syndrome criteria (n=20) were provided with a weight maintenance, controlled feeding base diet plus conventional canola oil, high-oleic acid canola oil (HOCO), or a control oil (control diet formulated to represent a Western diet fatty acid profile) for 6 weeks followed by washout periods of ≥4 weeks. The macronutrient profiles of the diets were: canola diet [17.5% monounsaturated fatty acid (MUFA), 9.2% polyunsaturated fatty acid (PUFA), 6.6% saturated fatty acid (SFA)], HOCO diet (19.1% MUFA, 7.0% PUFA, 6.4% SFA), and control diet (10.5% MUFA, 10.0% PUFA, 12.3% SFA). Fecal and blood samples were collected at study enrollment and at the end of each diet. Results: After 6 weeks, a trend toward a treatment effect on endpoint fecal propionic acid was observed ( P =0.09), with a trend toward a higher concentration following the control compared to the canola diet ( P =0.09). Acetic acid was increased from baseline following the control diet ( P =0.04). After the control diet only, fecal levels of propionic acid were positively correlated with blood levels of LDL-C, non-HDL-C, and apo B (r=0.52 to 0.64, P =0.003 to 0.02), with a trend for total cholesterol (r=0.39, P =0.10), and acetic acid was positively correlated with LDL-C and apo B levels (r=0.48 to 0.49, P =0.03 to 0.04), with a trend for non-HDL-C (r=0.44, P =0.06). No significant correlations between fecal SCFA and lipids and lipoproteins were observed after the two canola oil-based diets. Conclusions: In conclusion, these data suggest that the adverse effects of a contemporary Western diet fatty acid profile on circulating lipid and lipoprotein parameters compared to diets higher in unsaturated fat and lower in SFA may be mediated by gut-derived SCFA.

The Interpretation of Cholesterol Balance Derived Synthesis Data and Surrogate Noncholesterol Plasma Markers for Cholesterol Synthesis under Lipid Lowering Therapies

The cholesterol balance procedure allows the calculation of cholesterol synthesis based on the assumption that loss of endogenous cholesterol via fecal excretion and bile acid synthesis is compensated by de novo synthesis. Under ezetimibe therapy hepatic cholesterol is diminished which can be compensated by hepatic de novo synthesis and hepatic extraction of plasma cholesterol. The plasma lathosterol concentration corrected for total cholesterol concentration (R_Lath) as a marker of de novo cholesterol synthesis is increased during ezetimibe treatment but unchanged under treatment with ezetimibe and simvastatin. Cholesterol balance derived synthesis data increase during both therapies. We hypothesize the following. (1) The cholesterol balance data must be applied to the hepatobiliary cholesterol pool. (2) The calculated cholesterol synthesis value is the sum of hepatic de novo synthesis and the net plasma—liver cholesterol exchange rate. (3) The reduced rate of biliary cholesterol absorption is the major trigger for the regulation of hepatic cholesterol metabolism under ezetimibe treatment. Supportive experimental and literature data are presented that describe changes of cholesterol fluxes under ezetimibe, statin, and combined treatments in omnivores and vegans, link plasma R_Lath to liver function, and define hepatic de novo synthesis as target for regulation of synthesis. An ezetimibe dependent direct hepatic drug effect cannot be excluded.

Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism

The gut microbiota influences many aspects of host metabolism. We have previously shown that the presence of a gut microbiota remodels lipid composition. Here we investigated how interaction between gut microbiota and dietary lipids regulates lipid composition in the liver and plasma, and gene expression in the liver. Germ-free and conventionally raised mice were fed a lard or fish oil diet for 11 weeks. We performed lipidomics analysis of the liver and serum and microarray analysis of the liver. As expected, most of the variation in the lipidomics dataset was induced by the diet, and abundance of most lipid classes differed between mice fed lard and fish oil. However, the gut microbiota also affected lipid composition. The gut microbiota increased hepatic levels of cholesterol and cholesteryl esters in mice fed lard, but not in mice fed fish oil. Serum levels of cholesterol and cholesteryl esters were not affected by the gut microbiota. Genes encoding enzymes involved in cholesterol biosynthesis were downregulated by the gut microbiota in mice fed lard and were expressed at a low level in mice fed fish oil independent of microbial status. In summary, we show that gut microbiota-induced regulation of hepatic cholesterol metabolism is dependent on dietary lipid composition.

Sorghum extract exerts cholesterol-lowering effects through the regulation of hepatic cholesterol metabolism in hypercholesterolemic mice

The purpose of this study is to investigate that sorghum extract (SE) exerts cholesterol-lowering effects through the regulation of hepatic cholesterol metabolism-related protein expression. C57BL/6 mice were fed a modified AIN-93G diet (NC) with saline, or a modified AIN-93G diet with 2% cholesterol and 0.25% cholic acid with either saline (HC) or 600 mg SE/kg body weight (HC-SE). Levels of total cholesterol and triglycerides in serum and liver were significantly lower in HC-SE than in HC. The expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase, sterol regulatory elementary binding protein2 and fatty acid synthase were significantly lower, whereas phosphorylated AMP-activated protein kinase expression was significantly higher in HC-SE than in HC. Cholesterol 7-α hydroxylase expression was also significantly higher in mice given SE than in those given HC. These results suggest that the cholesterol-lowering effect of SE may be related to the regulation of hepatic cholesterol metabolism in this mouse model.

Cholesterol and lipoprotein metabolism: Early Career Committee contribution.

Cholesterol and lipoprotein metabolism: Early Career Committee contribution.

The mechanism of ABCG5/ABCG8 in biliary cholesterol secretion in mice

The main player in biliary cholesterol secretion is the heterodimeric transporter complex, ABCG5/ABCG8, the function of which is necessary for the majority of sterols secreted into bile. It is not clear whether the primary step in this process is flopping of cholesterol from the inner to the outer leaflet of the canalicular membrane, with desorption by mixed micelles, or decreasing of the activation energy required for cholesterol desorption from the outer membrane leaflet. In this study, we investigated these mechanisms by infusing Abcg8(+/+), Abcg8(+/-), and Abcg8(-/-) mice with hydrophilic and hydrophobic bile salts. In Abcg8(-/-) mice, this failed to substantially stimulate biliary cholesterol secretion. Infusion of the hydrophobic bile salt taurodeoxycholate also resulted in cholestasis, which was induced in Abcg8(-/-) mice at a much lower infusion rate compared with Abc8(-/-) and Abcg8(+/-) mice, suggesting a reduced cholesterol content in the outer leaflet of the canalicular membrane. Indeed, isolation of canalicular membranes revealed a reduction of 45% in cholesterol content under these conditions in Abcg8(-/-) mice. Our data support the model that ABCG5/ABCG8 primarily play a role in flopping cholesterol (and sterols) from the inner leaflet to the outer leaflet of the canalicular membrane.

Molecular mechanisms of altered cholesterol metabolism in rats with spontaneous focal glomerulosclerosis

Imai rats exhibit spontaneous focal glomerulosclerosis (FGS), which is marked by heavy proteinuria, severe hyperlipidemia, and progressive renal insufficiency beginning at 8 to 10 weeks of age. In an earlier study, we reported severe skeletal muscle and adipose tissue lipoprotein lipase, and very low-density lipoprotein (VLDL) receptor deficiencies, which account for elevated plasma VLDL and triglycerides in Imai rats at 34 weeks of age. In this study, we investigated key factors involved in cholesterol metabolism. Male Imai and Sprague-Dawley control rats were fed a regular rat chow and observed from age 8 through 34 weeks. Hepatic 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7alpha-hydroxylase, low-density lipoprotein (LDL) receptor and acyl Co A:cholesterol acyltransferase (ACAT) were measured by Western blot and plasma lecithin:cholesterol acyltransferase (LCAT) protein was measured by enzyme-linked immunosorbent assay (ELISA). At 34 weeks of age, the Imai rats showed severe proteinuria, hypoalbuminemia, 60% reduction in glomerular filtration rate (GFR), elevated plasma total and LDL cholesterol and LDL/high-density lipoprotein (HDL) ratio. Imai rats showed a twofold elevation of hepatic HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis, but no significant change in cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in cholesterol catabolism to bile acids. This was accompanied by and largely due to a threefold down-regulation of hepatic LDL receptor, which limits hepatic uptake of LDL; and a threefold up-regulation of hepatic ACAT (P < 0.01), which augments esterification of hepatocyte free cholesterol, thus, limiting cholesterol-mediated feedback regulation of cholesterol synthesis and catabolism. Moreover, plasma LCAT concentration was severely depressed (by fourfold) in Imai rats. This abnormality can impair HDL-mediated cholesterol transport from extrahepatic tissues to the liver. The study revealed marked abnormalities of the key proteins involved in regulation of hepatic cholesterol metabolism. These abnormalities can account for severe dysregulation of cholesterol metabolism in Imai rats with spontaneous FGS, which closely resembles FGS in humans.

Effect of obstructive jaundice on the regulation of hepatic cholesterol metabolism in the rat: Disappearance of abcg5 and abcg8 mRNA after bile duct ligation

The purpose of this study is to evaluate the effect of bile duct ligation (BDL) on changes of lipoprotein metabolism and hepatic gene expressions that are important for cholesterol metabolism. In male rats serum, very low-density lipoprotein cholesterol, low-density lipoprotein cholesterol and apolipoproteins B and E increased after 5 days of BDL compared with those of sham operation (control) group. Serum apolipoprotein A-IV concentration in the BDL group was lower than that in the control group. In both groups, there was no difference in hepatic lipid concentrations. Hepatic mRNA expressions of scavenger receptor B1, microsomal triglyceride transfer protein (mtp), HMG-coA reductase, cholesterol 7α-hydroxylase and multidrug resistance gene product 2 in the BDL group were significantly higher than that in the control group. The adipocyte determination and differentiation 1 mRNA expression in the BDL group was significantly lower than that in the control group. abcg5 and abcg8 mRNA expressions were remarkably decreased in the BDL group. In conclusion, in obstructive jaundice, metabolism of lipoprotein and proteins that are important for lipid metabolism are drastically changed probably for maintaining the hepatic lipid concentration. The remarkable down-regulation of the abcg5 and abcg8 may be an adaptive change reflecting the inability of biliary cholesterol excretion.

The molecular and metabolic basis of biliary cholesterol secretion and gallstone disease.

This article presents an up to date of selected aspects of the molecular mechanisms of cholesterol metabolism most likely involved in cholesterol gallstones disease, a highly prevalent disease in the Western world. The etiology of cholesterol cholelithiasis is considered to be multifactorial, with interaction of genetic and environmental factors. The production of supersaturated bile by the liver of cholesterol is a key early metabolic event underlying cholesterol lithogenesis. Regulation of hepatic cholesterol trafficking within the hepatocyte appears essential for the production of cholesterol supersaturated bile. Impaired sorting of metabolically active hepatic free cholesterol to the bile acid biosynthetic or lipoprotein production pathways leads to an increased availability of cholesterol for preferential channeling of cholesterol to the canalicular membrane and further secretion into bile. Many of these intrahepatic cholesterol trafficking steps are under genetic control and might be influenced by a variety of environmental factors. This review summarizes recent discoveries related to transhepatic cholesterol flux and biliary lipid secretion, which have provided new insights to the regulation of hepatic cholesterol metabolism as related to gallstone disease.

Regulation of hepatic cholesterol metabolism

Regulation of hepatic cholesterol metabolism

Differences between cholestyramine and colestimide (Colestilan), a novel hypolipidemic resin concerning regulation of hepatic cholesterol metabolism

Differences between cholestyramine and colestimide (Colestilan), a novel hypolipidemic resin concerning regulation of hepatic cholesterol metabolism

The influence of estrogen on hepatic cholesterol metabolism and biliary lipid secretion in rats fed fish oil

Both estrogen and dietary n-3 polyunsaturated fatty acids are known to be hypocholesterolemic, but appear to exert their effects by different mechanisms. In this study, the interaction between dietary fish oil (rich in n-3 polyunsaturated fatty acids) and estrogen in the regulation of hepatic cholesterol metabolism and biliary lipid secretion in rats was studied. Rats fed a low fat or a fish oil-supplemented diet for 21 days were injected with 17α-ethinyl estradiol (5 mg/kg body weight) or the vehicle only (control rats) once per day for 3 consecutive days. Estrogen-treatment led to a marked reduction in plasma cholesterol levels in fish oil-fed rats, which was greater than that observed with either estrogen or dietary fish oil alone. The expression of mRNA for cholesterol 7α-hydroxylase was decreased by estrogen in rats fed a low fat or a fish oil-supplemented diet, while the output of cholesterol (μmol/h/kg b.wt.) in the bile was unchanged in both groups. Cholesterol levels in the liver were increased by estrogen in rats given either diet, but there was a significant shift from cholesterol esterification to cholesteryl ester hydrolysis only in the fish oil-fed animals. Estrogen increased the concentration of cholesterol (μmol/ml) in the bile in rats fed the fish oil, but not the low fat diet. However, the cholesterol saturation index was unaffected. The output and concentration of total bile acid was also unaffected, but changes in the distribution of the individual bile acids were observed with estrogen treatment in both low fat and fish oil-fed groups. These results show that interaction between estrogen-treatment and dietary n-3 polyunsaturated fatty acids causes changes in hepatic cholesterol metabolism and biliary lipid secretion in rats, but does not increase the excretion of cholesterol from the body.

1994 Mack-Forster Award Lecture. Review. Studies on the regulation of hepatic cholesterol metabolism in humans.

1994 Mack-Forster Award Lecture. Review. Studies on the regulation of hepatic cholesterol metabolism in humans.

Regulation of hepatic cholesterol metabolism in the rat in vivo: effect of a synthetic fat-free diet on sterol synthesis and low-density lipoprotein transport.

A synthetic fat-free diet, previously shown to decrease hepatic cholesterol synthesis, was utilized to manipulate cholesterol balance in vivo in female Sprague-Dawley rats. A significant 65% decrease of hepatic cholesterol synthesis compared to controls was shown after 1 week of treatment, which remained constant during the following 3 weeks. The inhibitory effect of the diet was completely abolished by cholestyramine supplementation. At week 3 of the experimental diet, bile acid synthesis was reduced by 63%, this reduction being correlated with decreased recycling frequency of the bile acid pool. Hepatic clearance of low-density lipoprotein (LDL) was slightly decreased, with no changes in plasma cholesterol, hepatic LDL-cholesterol uptake and whole body LDL-cholesterol production. When cholesterol and saturated fatty acids were supplemented to the diets in the attempt to disclose alteration in LDL transport, LDL clearance was unaffected; plasma LDL-cholesterol and hepatic LDL-cholesterol uptake were increased, as a consequence of increased LDL-cholesterol production. On the other hand, hepatic cholesterol synthesis was further suppressed; bile acid synthesis was increased by cholesterol supplementation in the fat-free group, even if to subnormal levels. These findings suggest that: (1) bile acid synthesis is decreased by feeding a synthetic fat-free diet, probably due to slower recirculation of bile acids along the entero-hepatic axis in conditions of reduced functional need; (2) consequently, a significant reduction of hepatic cholesterol synthesis is observed with no changes in LDL-cholesterol uptake; (3) further supplementation of dietary cholesterol and saturated fats is compensated for by changes in the rates of cholesterol and bile acid synthesis, but not of LDL transport. The data confirm the existence of independent regulation for hepatic sterol synthesis and LDL transport in this species.

Regulation of Hepatic Cholesterol Metabolism in Man

The liver is a key element in regulating the amount of low density lipoprotein (LDL) cholesterol in plasma. The interference of cholestyramine treatment in the enterohepatic circulation of bile acids stimulates the activity of the rate limiting enzymatic step in bile acid biosynthesis (cholesterol 7 alpha-hydroxylase). This increases demand for cholesterol which is met by enhanced cholesterol biosynthesis (through the enzyme 3-hydroxy-3-methylglutaryl coenzyme A [HMG CoA] reductase) and by an increased expression of LDL receptors. Inhibition of HMG CoA reductase activity by treatment with specific inhibitors such as pravastatin enhances LDL receptor binding activity. Combination of the two treatments results in a significant stimulation of LDL receptor expression and a drastic reduction in the concentration of plasma LDL cholesterol. Thus, selective interference with bile acid enterohepatic circulation and cholesterol biosynthesis may be utilised to regulate plasma lipoprotein metabolism.

Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients.

To characterize the metabolic regulatory response to interruption of the enterohepatic circulation of bile acids, we examined the effects of cholestyramine treatment on the rate-limiting steps in cholesterol biosynthesis (HMG-CoA reductase) and bile acid production (cholesterol 7 alpha-hydroxylase) as well as on the heparin-sensitive binding of low density lipoproteins (LDL) (reflecting LDL receptor expression) in human liver. Altogether, 18 normolipidemic patients with uncomplicated cholesterol gallstone disease were treated with cholestyramine (8 g b.i.d.) for 2-3 weeks prior to cholecystectomy, and another 34 cholesterol gallstone patients served as untreated controls. Cholestyramine treatment stimulated cholesterol 7 alpha-hydroxylase more than sixfold, and increased both HMG-CoA reductase activity (552 +/- 60 pmol/min per mg protein vs 103 +/- 9 pmol/min per mg protein) and LDL receptor expression (6.1 +/- 0.8 ng/mg protein; n = 6 vs 2.2 +/- 0.3 ng/mg protein; n = 7). Moreover, there was a good correlation between HMG-CoA reductase activity and LDL receptor binding (rs = +0.71; n = 13), suggesting a simultaneous stimulatory effect to compensate for the increased hepatic cholesterol catabolism due to bile acid depletion caused by cholestyramine. Further evidence for this assumption was the finding of a significant relationship between cholesterol 7 alpha-hydroxylase activity and both LDL receptor expression (rs = +0.77; n = 13) and HMG-CoA reductase activity (rs = +0.76; n = 46). We conclude that in human liver a parallel stimulation of cholesterol synthesis and LDL receptor expression occurs in response to stimulation of bile acid synthesis.

Bile acid metabolism in familial dysbetalipoproteinaemia: studies in subjects with the apolipoprotein E‐2/2 phenotype

Bile acid kinetics and biliary lipid composition were determined in seven subjects with primary dysbetalipoproteinaemia. They were all homozygous for the apolipoprotein E isoform E-2 and six of them were hyperlipidaemic (type III hyperlipoproteinaemia). With or without hyperlipidaemia, the apo E-2/2 phenotype was associated with increased bile acid formation (mean increase compared with 32 normolipidaemic controls, 43%; P less than 0.025). The biliary lipid composition was not different from that seen in the controls. The results indicate that the uptake by the liver of apo E-containing remnant particles is of importance for the regulation of hepatic cholesterol metabolism in man. It is suggested that hepatic cholesterol synthesis is stimulated in dysbetalipoproteinaemia, and that this leads to a compensatory increase in bile acid synthesis.

24(S),25-Epoxycholesterol. Evidence consistent with a role in the regulation of hepatic cholesterogenesis.

Previously we showed that 24(S),25-epoxycholesterol is formed from acetate, via squalene 2,3(S),22(S),23-dioxide and 24(S),25-oxidolanosterol, during the normal course of cholesterol biosynthesis in S10 rat liver homogenate (Nelson, J. A., Steckbeck, S. R., and Spencer, T. A. (1981) J. Biol. Chem. 256, 1067-1068; Nelson, J. A., Steckbeck, S. R., and Spencer, T. A. (1981) J. Am. Chem. Soc. 103, 6974-6975). Herein we demonstrate that the nonsaponifiable extract from human liver tissue contains 24(S),25-epoxycholesterol in an amount approximately 10(-3) relative to cholesterol. We show that 24(S),25-epoxycholesterol, like many other oxygenated sterols, represses hydroxymethylglutaryl-CoA reductase activity in cultured cells and binds to the cytosolic oxysterol-binding protein. Furthermore, we show that this epoxide is not rapidly metabolized in cultured cells. These results suggest that 24(S),25-epoxycholesterol may participate in the regulation of hepatic cholesterol metabolism in vivo.

Hepatic cholesterogenesis in Chileans with cholesterol gallstone disease: Evidence for sex differences in the regulation of hepatic cholesterol metabolism

To test the hypothesis that hepatic cholesterol synthesis and concentration are specifically increased in women and men with cholesterol gallstone disease, we studied in a series of 24 surgical liver biopsy specimens, the rate of acetate incorporation into cholesterol and CO2, and the concentration of free and esterified cholesterol. There were 6 women in each group of 12 control and 12 gallstone patients. The rates of hepatic cholesterogenesis and CO2 production were similar in control and gallstone patients. Therefore, hypersecretion of biliary cholesterol, a common finding in Chileans with gallstones, is not pathogenically linked to a basic biochemical abnormality in the hepatic cholesterogenic pathway. The concentrations of hepatic cholesterol were similar in patients with and without gallstones. However, there were significant increments of 37% in the free fraction and 78% in the esterified fraction of hepatic cholesterol in female subjects, irrespectively of the presence of cholelithiasis. These results suggest that the flux of lipoprotein cholesterol to the liver is increased in women. The regulatory mechanism of hepatic cholesterogenesis is less sensitive to cellular cholesterol in women than in men, as the fluxes of acetate into cholesterol are similar in both sexes, in spite of the significant increase of hepatic cholesterol in females. These findings demonstrate that sex factors play a fundamental role in the regulation of cholesterol metabolism in the human liver.