Biliary cholesterol excretion: A novel mechanism that regulates dietary cholesterol absorption

Sehayek, Ephraim; Ono, Jennie G.; Shefer, Sarah; Nguyen, Lien; Wang, Nan; Batta, Ashok K.; Salen, Gerald; Smith, Jonathan; Tall, Alan R.; Breslow, Jan L.

doi:10.1073/pnas.95.17.10194

Cited by 160 publications

(125 citation statements)

References 35 publications

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“…1D). These findings are consistent with previous studies showing that increased dietary cholesterol leads to significant accumulation of cholesterol in the plasma and liver of mice despite compensatory mechanisms such as down-regulation of hepatic cholesterol synthesis and enhanced biliary sterol secretion (42)(43)(44). Hepatic Overexpression of hABCG5/G8 Enhances Biliary Sterol Secretion in Liver G5/G8 Transgenic Mice on the 4% C Diet-As discussed above, on the 4% C diet, not only is ABCG5/G8 gene expression enhanced but in addition, hepatic cholesterol concentrations and hence, the amount of cholesterol substrate available for transport by liver ABCG5/G8 is increased.…”

Section: Hepatobiliary Sterol Concentrations Sterol Secretion Ratessupporting

confidence: 82%

Hepatic ABCG5 and ABCG8 Overexpression Increases Hepatobiliary Sterol Transport but Does Not Alter Aortic Atherosclerosis in Transgenic Mice

Basso

Shamburek

et al. 2004

Journal of Biological Chemistry

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The individual roles of hepatic versus intestinal ABCG5 and ABCG8 in sterol transport have not yet been investigated. To determine the specific contribution of liver ABCG5/G8 to sterol transport and atherosclerosis, we generated transgenic mice that overexpress human ABCG5 and ABCG8 in the liver but not intestine (liver G5/G8-Tg) in three different genetic backgrounds: C57Bl/6, apoE-KO, and low density lipoprotein receptor (LDLr)-KO. Hepatic overexpression of ABCG5/G8 enhanced hepatobiliary secretion of cholesterol and plant sterols by 1.5-2-fold, increased the amount of intestinal cholesterol available for absorption and fecal excretion by up to 27%, and decreased the accumulation of plant sterols in plasma by ϳ25%. However, it did not alter fractional intestinal cholesterol absorption, fecal neutral sterol excretion, hepatic cholesterol concentrations, or hepatic cholesterol synthesis. Consequently, overexpression of ABCG5/G8 in only the liver had no effect on the plasma lipid profile, including cholesterol, HDL-C, and non-HDL-C, or on the development of proximal aortic atherosclerosis in C57Bl/6, apoE-KO, or LDLr-KO mice. Thus, liver ABCG5/G8 facilitate the secretion of liver sterols into bile and serve as an alternative mechanism, independent of intestinal ABCG5/G8, to protect against the accumulation of dietary plant sterols in plasma. However, in the absence of changes in fractional intestinal cholesterol absorption, increased secretion of sterols into bile induced by hepatic overexpression of ABCG5/G8 was not sufficient to alter hepatic cholesterol balance, enhance cholesterol removal from the body or to alter atherogenic risk in liver G5/G8-Tg mice. These findings demonstrate that overexpression of ABCG5/G8 in the liver profoundly alters hepatic but not intestinal sterol transport, identifying distinct roles for liver and intestinal ABCG5/G8 in modulating sterol metabolism.Sitosterolemia, also known as phytosterolemia (1-9) is a rare genetic disorder characterized by elevated plasma and tissue levels of plant, shellfish, and animal sterols and the development of tendon and tuberous xanthomas, hemolytic episodes, arthritis, and premature coronary artery disease. The ATPbinding cassette (ABC) 1 half-transporters ABCG5 and ABCG8 (ABCG5/G8) have been recently identified as the genes defective in sitosterolemia (10 -12). The increased plasma and tissue levels of animal and plant sterols found in sitosterolemic patients have been attributed to enhanced absorption and decreased biliary excretion (1-4, 6, 8, 13-16). Unlike cholesterol, sitosterol accumulation does not inhibit HMGCoA reductase activity in human monocyte-derived macrophages (17). The inadequate down-regulation of HMGCoA reductase activity by plant sterols may promote foam cell formation and explain, in part, the increased risk of atherosclerosis in sitosterolemia (17).Several lines of evidence implicate ABCG5/G8 in intestinal and biliary sterol transport. First, ABCG5/G8 are expressed in the liver and small intestine and, to a lesser degree, in th...

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Section: Hepatobiliary Sterol Concentrations Sterol Secretion Ratessupporting

confidence: 82%

Hepatic ABCG5 and ABCG8 Overexpression Increases Hepatobiliary Sterol Transport but Does Not Alter Aortic Atherosclerosis in Transgenic Mice

Basso

Shamburek

et al. 2004

Journal of Biological Chemistry

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“…SR-BI knockout mice show a 45% decrease in biliary cholesterol secretion rates, 16 whereas SR-BI overexpression increases biliary cholesterol content. 8,9,25 However, thus far the obligate heterodimeric ATP-binding cassette transporters Abcg5/Abcg8 have been characterized to represent the major and supposedly ratecontrolling transport system for cholesterol excretion into bile. The role of Abcg5/Abcg8 has been substantiated by showing that overexpression of these transporters results in increased biliary cholesterol secretion 19 and that knockouts for Abcg5 or Abcg8 have a decrease in biliary cholesterol secretion rates by about 75%.…”

Section: Discussionmentioning

confidence: 99%

Scavenger receptor class B type I mediates biliary cholesterol secretion independent of ATP-binding cassette transporter g5/g8 in mice

et al. 2009

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Scavenger receptor class B type I (SR-BI) mediates selective uptake of cholesterol from highdensity lipoprotein (HDL) particles by the liver and influences biliary cholesterol secretion. However, it is not clear, if this effect is direct or indirect. The aim of this study was to determine the impact of SR-BI on biliary cholesterol secretion, especially in a functional context with ATP-binding cassette transporter g5 (Abcg5)/Abcg8 and Abcb4. SR-BI was overexpressed by means of adenovirus (AdSR-BI) in livers of wild-type, liver X receptor-null (Lxr ؊/؊ ), Abcg5 ؊/؊ , and Abcb4 ؊/؊ mice. Consistent with previous reports, AdSR-BI decreased plasma HDL cholesterol levels in all models (P < 0.001). Hepatic cholesterol content increased (at least P < 0.05), whereas expression of sterol regulatory element binding protein 2 target genes was decreased (at least P < 0.05,) and established Lxr target genes were unaltered. Biliary cholesterol secretion was increased by AdSR-BI in wild-type as well as in Lxr ؊/؊ and Abcg5 ؊/؊ mice, and considerably less in Abcb4 ؊/؊ mice (each P < 0.001), independent of bile acid and phospholipid secretion. T he scavenger receptor class B type I (SR-BI) has been characterized as a receptor that mediates cholesterol transport across membranes. 1,2 In nonpolarized cells, namely macrophages and the hepatoma cell line Fu5AH, SR-BI expression either results in selective uptake of cholesterol, mainly from high-density lipoprotein (HDL), or in cholesterol efflux toward suitable acceptors. [3][4][5][6] In hepatocytes, which is a highly polarized cell type, SR-BI is the main receptor responsible for selective uptake of cholesterol from plasma HDL. 7 Consequently, hepatic overexpression of SR-BI results in decreased plasma HDL cholesterol levels, 8-10 whereas SR-BI knockout mice have increased plasma HDL cholesterol. 11,12 Interestingly, hepatocyte SR-BI appears to accelerate reverse cholesterol transport in vivo in the face of decreased plasma HDL cholesterol levels, 13 which is in line with studies demonstrating that hepatic SR-BI expression protects against atherosclerosis development in mouse models. 14,15 Hepatic SR-BI expression is also linked to biliary cholesterol

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“…Direct measurement of the latter has failed to show consistent effects of other statins. 7,13,14 However, a decrease in biliary cholesterol secretion could also lead to an increase in cholesterol absorption, as shown in mice 15 and in dietary studies in humans. 16 Low cholesterol absorption efficiency in obesity may be because of an increased biliary cholesterol pool that competes with dietary cholesterol and noncholesterol sterols for intestinal absorption.…”

Section: Discussionmentioning

confidence: 99%

Effect of a statin on hepatic apolipoprotein B-100 secretion and plasma campesterol levels in the metabolic syndrome

et al. 2003

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OBJECTIVE:We aimed to study the effect of atorvastatin, a statin, on cholesterol synthesis and absorption and VLDL-apoB metabolism in obese men with the metabolic syndrome. METHODS: A total of 25 dyslipidaemic obese men were randomized to atorvastatin (n ¼ 13) (40 mg/day) or matching placebo (n ¼ 12) for 6 weeks. Hepatic secretion and fractional catabolic rate (FCR) of VLDL-apoB was measured using an intravenous bolus of d 3 -leucine before and after treatment. ApoB isotopic enrichment was measured using GCMS and multicompartmental modelling. Plasma lathosterol: cholesterol and campesterol:cholesterol ratios were determined to assess cholesterol synthesis and cholesterol absorption, respectively. RESULTS: Compared with placebo, atorvastatin significantly decreased (Po0.05) total cholesterol, triglyceride, LDL-cholesterol and VLDL-apoB. Plasma lathosterol:cholesterol ratio decreased from 26.472.4 to 8.870.8, while the campesterol:cholesterol ratio increased from 26.574.4 to 38.675.8 (Po0.01). Atorvastatin also increased VLDL-apoB FCR from 3.8270.33 to 6.3070.75 pools/day (Po0.01), but did not significantly alter VLDL-apoB secretion (12.871.7 to 13.872.0 mg/kg/day). CONCLUSIONS: In obesity, atorvastatin inhibits cholesterogenesis but increases intestinal cholesterol absorption. The increased cholesterol absorption may counteract the inhibitory effect on hepatic VLDL-apoB secretion, but it does not apparently influence enhanced catabolism of VLDL-apoB.

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Biliary cholesterol excretion: A novel mechanism that regulates dietary cholesterol absorption

Abstract: The regulation of dietary cholesterol absorption was examined in C57BL͞6 and transgenic mice with liver overexpression of the scavenger receptor BI (SR-BI Tg). In

Cited by 160 publications

References 35 publications

Hepatic ABCG5 and ABCG8 Overexpression Increases Hepatobiliary Sterol Transport but Does Not Alter Aortic Atherosclerosis in Transgenic Mice

Hepatic ABCG5 and ABCG8 Overexpression Increases Hepatobiliary Sterol Transport but Does Not Alter Aortic Atherosclerosis in Transgenic Mice

Scavenger receptor class B type I mediates biliary cholesterol secretion independent of ATP-binding cassette transporter g5/g8 in mice

Effect of a statin on hepatic apolipoprotein B-100 secretion and plasma campesterol levels in the metabolic syndrome

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