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

Abstract

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 ∼25%. 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. 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 ∼25%. 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 (1Bhattacharyya A.K. Connor W.E. J. Clin. Investig. 1974; 53: 1033-1143Crossref PubMed Scopus (462) Google Scholar, 2Shulman R. Bhattacharyya A. Connor W. Fredrickson D. N. Eng. J. Med. 1976; 294: 482-483Crossref PubMed Scopus (96) Google Scholar, 3Miettinen T.A. Eur. J. Clin. Investig. 1980; 10: 27-35Crossref PubMed Scopus (197) Google Scholar, 4Lin H.-J. Wang C. Salen G. Lam K.-C. Chan T.-K. Metabolism. PubMed Scopus Google Scholar, G. J. PubMed Google Scholar, Connor J. Clin. Investig. PubMed Scopus (96) Google Scholar, D. The of Scholar, G. J. PubMed Google Scholar, PubMed Scopus Google genetic by plasma and of and sterols and the development of and and The density low density liver cholesterol body ABCG5 and ABCG8 have been as the in J. R. PubMed Scopus Google Scholar, A. G. PubMed Scopus Google Scholar, A. A. Salen G. A. J. PubMed Scopus Google The increased plasma and of and plant sterols in have been to enhanced absorption and decreased excretion (1Bhattacharyya A.K. Connor W.E. J. Clin. Investig. 1974; 53: 1033-1143Crossref PubMed Scopus (462) Google Scholar, 2Shulman R. Bhattacharyya A. Connor W. Fredrickson D. N. Eng. J. Med. 1976; 294: 482-483Crossref PubMed Scopus (96) Google Scholar, 3Miettinen T.A. Eur. J. Clin. Investig. 1980; 10: 27-35Crossref PubMed Scopus (197) Google Scholar, 4Lin H.-J. Wang C. Salen G. Lam K.-C. Chan T.-K. Metabolism. PubMed Scopus Google Scholar, Connor J. Clin. Investig. PubMed Scopus (96) Google Scholar, G. J. PubMed Google Scholar, G. A.K. J. PubMed Google Scholar, G. Google Scholar, D. J. PubMed Google Scholar, A.K. Connor W.E. PubMed Google cholesterol, accumulation not in human Salen G. Metabolism. PubMed Scopus Google The of by plant sterols and in the increased risk of atherosclerosis in Salen G. Metabolism. PubMed Scopus Google of ABCG5/G8 in intestinal and sterol ABCG5/G8 in the liver and intestine to in the J. R. PubMed Scopus Google Scholar, A. A. Salen G. A. J. PubMed Scopus Google Scholar, Salen G. J. PubMed Google Scholar, C. J. PubMed Scopus Google Scholar, R. N. R. A.K. Salen G. PubMed Scopus Google and A. R. PubMed Scopus Google and have been to to the of as A. J. Clin. Investig. PubMed Scopus Google in and in have that ABCG5/G8 by in lipid and sterol metabolism. of receptor in sterol enhance ABCG5/G8 in C. J. PubMed Scopus Google and mice ABCG5/G8 in the liver and intestine of but not mice J. R. PubMed Scopus Google of ABCG5 and ABCG8 in mice to increased intestinal cholesterol absorption and decreased bile cholesterol J. D. A. PubMed Scopus Google to that of overexpression of human ABCG5/G8 the cholesterol by and dietary sterol absorption by in transgenic mice J. J. Clin. Investig. PubMed Scopus Google in mice and have an ABCG5 and ABCG8 and changes in cholesterol secretion and intestinal cholesterol absorption A.K. Clin. Scholar, PubMed Scopus Google Scholar, A. R. A.K. J. PubMed Scopus Google Thus, ABCG5/G8 that in the excretion of cholesterol and sterols from the we the of transgenic mice that overexpress in the liver of C57Bl/6, apoE-KO, and receptor mice. the contribution of liver ABCG5/G8 to hepatobiliary sterol transport and the of hepatic overexpression of on the development of demonstrate for liver ABCG5/G8 in sterol secretion into bile and in the plasma of plant sterols in plasma. However, hepatic overexpression of ABCG5/G8 did not fractional intestinal cholesterol absorption facilitate the of cholesterol from liver G5/G8-Tg mice that of mice. increased hepatobiliary sterol overexpression of ABCG5/G8 in the liver did not alter hepatic cholesterol or changes in liver or in hepatic that to changes in the plasma lipoprotein and aortic atherosclerosis in C57Bl/6, and LDLr-KO mice. These findings for hepatic and intestinal ABCG5/G8, and that increased of intestinal as as hepatic ABCG5/G8 to the of body cholesterol and atherogenic of ABCG5/G8 and the ABCG5 and ABCG8 A. C. PubMed Scopus Google was to transgenic mice in the as G. C. J. J. Clin. Investig. PubMed Scopus Google of the was by of and by ABCG5/G8 available different and for To or LDLr-KO mice transgenic mice or LDLr-KO mice in the to by the and of the of and transgenic mice of on the as the cholesterol, and or cholesterol cholesterol, and for of to To the of aortic and transgenic mice on the as A. D. PubMed Scopus Google Scholar, J. J. PubMed Google and LDLr-KO mice on cholesterol, and by to sterol was in of mice for and was from and mice the was to by that human and ABCG5 and ABCG8 human only ABCG5 and ABCG8 and only human ABCG5 and ABCG8 human and as C. G. J. Fredrickson PubMed Scopus Google Scholar, A. J. J. N. J. PubMed Scopus Google and to was the to the and ABCG5/G8 by the and for of available was by and of was and lipid as G. C. J. J. Clin. Investig. PubMed Scopus Google Scholar, C. G. J. Fredrickson PubMed Scopus Google was as the cholesterol in the plasma of the or of by by as G. C. J. J. Clin. Investig. PubMed Scopus Google Scholar, C. G. J. Fredrickson PubMed Scopus Google liver as G. N. Chan A. R. G. R. J. PubMed Scopus Google on and against human and from A. J. J. N. J. PubMed Scopus Google The was or to by A. J. J. N. J. PubMed Scopus Google and by and of plasma from as G. C. J. J. Clin. Investig. PubMed Scopus Google Scholar, C. G. J. Fredrickson PubMed Scopus Google Scholar, A. J. J. N. J. PubMed Scopus Google and different for for and body The by an was and the bile was an of and an of to the of but to the of the was for by bile sterols by as and by the cholesterol the bile was the of of plasma and bile for in and by of J. PubMed Google for and to in and into to the of J. PubMed Scopus Google The was of The was and the sterol from mice of on the for cholesterol absorption by the plasma J. 1974; PubMed Google Scholar, J. PubMed Google of in cholesterol in the liver and intestine of of as J. PubMed Google Scholar, J. Google Hepatic and of neutral sterols in liver and was by as J. PubMed Google the of liver and of was in of by of and of J. PubMed Google Scholar, W. J. J. PubMed Google of the in sterols in and an of the was and in The of neutral sterols in was by excretion of cholesterol and was by and cholesterol in by of the in for of hepatic and fecal neutral sterols an as W. J. J. PubMed Google of and of and as A. D. PubMed Scopus Google of the aortic and for neutral and for to determine the of for A. D. PubMed Scopus Google as and transgenic mice by and as of was by the of ABCG5/G8 and on and ABCG8 in liver and intestine have roles in and intestinal sterol transport J. R. PubMed Scopus Google Scholar, A. G. PubMed Scopus Google Scholar, A. A. Salen G. A. J. PubMed Scopus Google Scholar, J. D. A. PubMed Scopus Google but the independent contribution of hepatic not yet been investigated. generated transgenic of the human ABCG5 and ABCG8 of by the A. C. PubMed Scopus Google into mice. that and human ABCG5/G8 that ABCG5 and ABCG8 was increased in the liver but not intestine of liver G5/G8-Tg mice mice and the of human ABCG5 and ABCG8 in the but not of liver G5/G8-Tg mice. ABCG5/G8 overexpression did not alter or in the liver or intestine of liver G5/G8-Tg mice These findings by or not The of in liver G5/G8-Tg mice to the contribution of liver ABCG5 and ABCG8 to sterol transport and the of hepatic ABCG5/G8 overexpression on hepatic and intestinal sterol transport in mice low sterol Hepatic ABCG5/G8 overexpression did not the hepatobiliary sterol versus or secretion versus of liver G5/G8-Tg mice that of versus as as bile secretion versus also in liver G5/G8-Tg and mice. the cholesterol, plant liver G5/G8-Tg and mice of of cholesterol and of plant sterols cholesterol absorption, by the plasma J. 1974; PubMed Google Scholar, J. PubMed Google was in liver G5/G8-Tg mice the amount of cholesterol available for intestinal absorption and fecal excretion as dietary in liver G5/G8-Tg and mice as as the of cholesterol as intestinal cholesterol cholesterol in liver G5/G8-Tg and mice neutral sterol excretion, on low sterol cholesterol, plant of dietary plant was in liver G5/G8-Tg of fecal versus of fecal mice. no in the fecal cholesterol excretion was of fecal and of fecal mice. no in the hepatic cholesterol or plasma and or plant sterol in liver G5/G8-Tg and sterol concentrations, sterol secretion and intestinal cholesterol absorption in liver G5/G8-Tg and sterol sterol secretion sterol secretion cholesterol intestinal cholesterol cholesterol in Thus, on the low sterol the increased of human ABCG5/G8 did not alter the sterol excretion or intestinal cholesterol absorption by the ABCG5 and ABCG8 in liver G5/G8-Tg mice. of ABCG5/G8 and Hepatic and in G5/G8-Tg and the of the on and liver G5/G8-Tg mice. that and human ABCG5/G8 the the increased of ABCG5 and ABCG8 in the liver and intestine of liver G5/G8-Tg and mice and that the enhanced hepatic of ABCG5 and ABCG8 in and mice and of human ABCG5/G8 in mice. on the human ABCG5/G8 was increased in liver but not intestine of liver G5/G8-Tg mice mice the low sterol the the plasma of and in versus and increased hepatic cholesterol versus of liver G5/G8-Tg and dietary cholesterol also the sterol secretion of and liver G5/G8-Tg mice mice on an versus on the the increased absorption of dietary cholesterol and of plasma cholesterol was in the plasma of and and the of and in and mice in mice the low sterol These findings that increased dietary cholesterol to accumulation of cholesterol in the plasma and liver of mice as of hepatic cholesterol and enhanced sterol secretion PubMed Scopus Google Scholar, J. Google Scholar, Wang N. A.K. Salen G. A. PubMed Scopus Google Hepatic of in on the on the not only ABCG5/G8 enhanced but in hepatic cholesterol and the amount of cholesterol available for transport by liver ABCG5/G8 These to findings that in to the overexpression of ABCG5/G8 in liver increased sterol by versus and secretion by versus in liver G5/G8-Tg mice on the Hepatic ABCG5/G8 overexpression also increased the in bile (liver G5/G8-Tg in versus or bile versus secretion and the the low sterol the intestinal cholesterol absorption was in and liver G5/G8-Tg mice that the amount of dietary cholesterol increased fractional intestinal cholesterol absorption decreased J. PubMed Scopus Google on the no in intestinal cholesterol absorption was the These findings demonstrate that hepatic overexpression of ABCG5/G8 sterol secretion but not alter intestinal cholesterol absorption in mice. the hepatic and intestinal sterol transport in and liver G5/G8-Tg mice. the cholesterol and plant of dietary cholesterol and of plant sterols dietary cholesterol, the contribution of cholesterol versus to the of intestinal cholesterol available for absorption from dietary and for and liver G5/G8-Tg on the Hepatic overexpression of ABCG5/G8 the hepatobiliary sterol secretion versus the amount of sterol by in versus mice. However, the hepatobiliary sterols by liver G5/G8-Tg mice had on the amount of intestinal cholesterol available for absorption and fecal excretion in the absence of changes in the fractional intestinal cholesterol absorption (liver and the amount of cholesterol from the and to the liver in liver G5/G8-Tg versus mice in in mice did not the increased sterols by liver G5/G8-Tg versus mice by the intestine in the neutral fecal sterol excretion versus and fecal cholesterol excretion versus in liver G5/G8-Tg versus mice on the alter the fractional cholesterol absorption by the we also intestinal cholesterol absorption the cholesterol J. PubMed Scopus Google The of cholesterol by the of cholesterol in the from the amount of cholesterol in the intestine of and mice cholesterol for and mice the amount of cholesterol was the cholesterol and the fractional cholesterol absorption versus intestinal cholesterol absorption was not decreased in liver G5/G8-Tg versus mice by the fractional intestinal cholesterol absorption the cholesterol that the in sterol secretion in mice was by in the amount of cholesterol from the and to the liver in liver Thus, hepatic overexpression of ABCG5/G8 enhanced hepatobiliary sterol secretion on the it did not alter the cholesterol the liver removal of body cholesterol from liver G5/G8-Tg versus mice. Consequently, the increased sterol secretion in liver G5/G8-Tg mice was not in the hepatic cholesterol or in liver of the and mice not Hepatic of in on the of the plasma lipid no transgenic and mice on the Hepatic overexpression of ABCG5/G8 the plasma and liver G5/G8-Tg mice that overexpression of ABCG5 and ABCG8 only in liver sufficient to the accumulation of plant sterols in plasma. Hepatic of in on the effect of ABCG5 and ABCG8 overexpression on aortic in we liver G5/G8-Tg and mice on cholesterol, for A. D. PubMed Scopus Google Scholar, J. J. PubMed Google to in mice. the plasma and plasma increased in three not However, no in the plasma lipid of liver G5/G8-Tg mice of the not the aortic in and liver G5/G8-Tg mice the alters sterol absorption J. PubMed Google and for hepatic cholesterol J. PubMed Google Scholar, N. Eur. J. PubMed Scopus Google from the overexpression of ABCG5 and we no in sterol liver G5/G8-Tg and mice on the of the of hepatic ABCG5 and ABCG8 overexpression on sterol transport and aortic atherosclerosis in that not of dietary to mice liver G5/G8-Tg mice to liver G5/G8-Tg mice. in mice on human in the liver but not the intestine of liver G5/G8-Tg mice and of ABCG5 and ABCG8 was liver G5/G8-Tg and mice in the liver and the intestine The plasma cholesterol, and cholesterol versus as as the hepatic cholesterol versus of and liver G5/G8-Tg mice increased and mice on an and liver G5/G8-Tg mice had increased sterol secretion the mice versus Hepatic of in but the or in of ABCG5 and ABCG8 in liver increased the sterol versus and secretion versus in liver G5/G8-Tg mice on the enhanced hepatobiliary sterol secretion in liver G5/G8-Tg versus mice in the of increased hepatic cholesterol liver G5/G8-Tg and mice on the amount of cholesterol available for ABCG5/G8 the and bile secretion and liver G5/G8-Tg mice not intestinal cholesterol absorption was not decreased in liver G5/G8-Tg versus in for increased cholesterol absorption that did not was in liver G5/G8-Tg versus mice on the These demonstrate that hepatic overexpression of ABCG5/G8 sterol but not intestinal sterol the hepatic and intestinal transport of sterols in and liver G5/G8-Tg mice. the of mice of cholesterol and and (liver G5/G8-Tg of sterols in the bile mice the contribution of cholesterol to the of intestinal cholesterol available for absorption from dietary hepatobiliary and liver G5/G8-Tg and liver G5/G8-Tg Thus, the hepatobiliary sterol by liver G5/G8-Tg mice versus an of in the amount of intestinal cholesterol available for absorption and fecal intestinal cholesterol in liver G5/G8-Tg mice mice and the fractional intestinal cholesterol absorption in liver G5/G8-Tg was not decreased the amount of cholesterol from the and to the liver to increased in liver G5/G8-Tg mice. an in the intestinal cholesterol absorption liver G5/G8-Tg versus versus mice. Thus, the increased hepatic cholesterol the in liver G5/G8-Tg mice was by of cholesterol to the liver from absorption and transport of intestinal cholesterol the sterol was to the in of intestinal cholesterol and liver G5/G8-Tg mice fecal cholesterol excretion The fecal neutral sterol excretion and liver G5/G8-Tg and fecal cholesterol excretion and liver in and liver G5/G8-Tg mice. These that in cholesterol secretion and in intestinal cholesterol, in the absence of changes in fractional intestinal cholesterol absorption hepatic overexpression of ABCG5/G8 did not alter the cholesterol the liver the excretion of fecal cholesterol of liver of liver G5/G8-Tg versus mice. the increased sterol secretion in liver G5/G8-Tg mice was not changes in hepatic cholesterol liver cholesterol versus liver or changes in liver of the and mice not no in the plasma of HDL-C, and or in the plasma and and liver G5/G8-Tg mice. Hepatic overexpression of ABCG5/G8 the and in plasma of liver G5/G8-Tg mice To the increased sterol secretion induced by hepatic ABCG5/G8 overexpression atherosclerosis, we the proximal of and and liver G5/G8-Tg and mice an by the absence of changes in the plasma lipid profile, no in proximal aortic the of and or of liver G5/G8-Tg and mice. of LDLr-KO also the of hepatic ABCG5 and ABCG8 overexpression on sterol transport and aortic atherosclerosis in by LDLr-KO mice liver G5/G8-Tg mice. in and human in the liver but not intestine of liver LDLr-KO mice and of ABCG5 and ABCG8 was in liver and intestine the the plasma cholesterol versus and hepatic cholesterol versus of LDLr-KO and liver LDLr-KO mice increased mice on an LDLr-KO and liver LDLr-KO mice had increased sterol secretion the mice versus Hepatic of in LDLr-KO but in LDLr-KO of ABCG5 and ABCG8 in liver increased the sterol secretion in liver G5/G8-Tg LDLr-KO mice LDLr-KO mice versus the and bile secretion LDLr-KO and LDLr-KO mice not and no in fractional intestinal cholesterol absorption was LDLr-KO and liver LDLr-KO mice the hepatic and intestinal sterol transport in LDLr-KO and liver G5/G8-Tg LDLr-KO mice. the cholesterol, plant of mice of cholesterol the cholesterol and liver G5/G8-Tg to the of intestinal cholesterol available for absorption and fecal excretion from dietary in LDLr-KO and liver G5/G8-Tg LDLr-KO The hepatobiliary sterols by liver G5/G8-Tg LDLr-KO mice versus LDLr-KO mice an in the of intestinal cholesterol available for absorption and fecal excretion in LDLr-KO mice. the fractional intestinal cholesterol absorption was not decreased in liver G5/G8-Tg LDLr-KO and LDLr-KO the amount of cholesterol from the and to the liver was increased in liver G5/G8-Tg LDLr-KO versus LDLr-KO mice Thus, the increased hepatic cholesterol in liver G5/G8-Tg LDLr-KO mice was by increased of cholesterol to the liver from absorption and transport of intestinal cholesterol cholesterol excretion (liver G5/G8-Tg and was not enhanced in liver G5/G8-Tg LDLr-KO versus LDLr-KO mice. for LDLr-KO and liver G5/G8-Tg LDLr-KO mice the amount of cholesterol was the cholesterol and LDLr-KO the fractional cholesterol absorption versus in the of intestinal cholesterol in liver G5/G8-Tg LDLr-KO mice versus LDLr-KO mice. These in cholesterol secretion and an in intestinal cholesterol, in the absence of changes in fractional intestinal cholesterol absorption hepatic overexpression of ABCG5/G8 did not alter the cholesterol the liver the excretion of fecal cholesterol in liver G5/G8-Tg LDLr-KO versus LDLr-KO mice. the increased sterol excretion in liver G5/G8-Tg LDLr-KO mice was not decreased hepatic cholesterol increased hepatic cholesterol versus liver G5/G8-Tg or changes in liver of the and LDLr-KO mice not of the plasma lipid no in the plasma of HDL-C, and on not or and LDLr-KO and liver G5/G8-Tg LDLr-KO mice. on the no in the plasma of as as plant not hepatic overexpression of ABCG5/G8 the as as the in plasma of liver G5/G8-Tg LDLr-KO LDLr-KO mice on the To the increased sterol excretion induced by ABCG5/G8 overexpression atherosclerosis, we the proximal of and and LDLr-KO and liver G5/G8-Tg LDLr-KO mice in proximal aortic in or liver G5/G8-Tg LDLr-KO LDLr-KO mice on for or that ABCG5 and ABCG8 in liver and intestine that to transport sterols J. R. PubMed Scopus Google Scholar, A. G. PubMed Scopus Google Scholar, A. A. Salen G. A. J. PubMed Scopus Google Scholar, J. D. A. PubMed Scopus Google Scholar, J. J. Clin. Investig. PubMed Scopus Google the individual roles of hepatic versus intestinal ABCG5/G8 in sterol transport and atherosclerosis have not yet been we the of transgenic mice that overexpress human ABCG5 and ABCG8 in liver of apoE-KO, and LDLr-KO mice of transgenic we to the specific of hepatic to sterol transport and atherosclerosis different dietary Hepatic ABCG5/G8 overexpression increased sterol and secretion and accumulation of plant sterols in plasma of dietary or hepatic sterol of ABCG5/G8 did intestinal cholesterol absorption, hepatic cholesterol concentrations, fecal sterol excretion, plasma cholesterol, or lipoprotein Consequently, hepatic ABCG5/G8 overexpression did not protect against the development of aortic in three independent of of demonstrate that the and and in ABCG5/G8 increased by in liver of mice in mice. of sterols into bile was increased in liver G5/G8-Tg on the for liver G5/G8-Tg mice on an and for liver G5/G8-Tg mice on of sterol the Hepatic overexpression of ABCG5/G8 also to plant sterol and plant in plasma of mice on mice in the the hepatic sterol was mice on an the sterol secretion for liver G5/G8-Tg and mice These of of hepatic sterols by the and that in to changes in ABCG5/G8 the amount of hepatic sterols available for transport for ABCG5/G8 and liver G5/G8-Tg mice had bile and secretion that hepatic ABCG5/G8 not in transport of demonstrate that liver ABCG5/G8 to of hepatic cholesterol and plant but not bile or that the in sterol to hepatic ABCG5/G8 overexpression in transgenic mice was that for the human ABCG5/G8 transgenic mice generated by J. J. Clin. Investig. PubMed Scopus Google in liver and These to different ABCG5/G8 from of the into the in generated ABCG5/G8 transgenic the sterol by the bile also of hepatobiliary sterol secretion J. J. Clin. Investig. PubMed Scopus Google sterol in to the that changes in and secretion or of to in of bile for ABCG5/G8 in the A. R. PubMed Scopus Google the bile to and also of sterol secretion for of cholesterol Hepatic overexpression of ABCG5/G8 did not alter fractional intestinal cholesterol absorption by the plasma or the cholesterol J. 1974; PubMed Google Scholar, J. PubMed Google in genetic on dietary have that fractional intestinal cholesterol absorption by changes in dietary cholesterol and lipid secretion J. PubMed Scopus Google Scholar, N. J. PubMed Google increased intestinal cholesterol in the plasma and fecal as as intestinal sterol we also cholesterol absorption the cholesterol J. PubMed Scopus Google we demonstrate that hepatic overexpression not intestinal cholesterol The increased amount of intestinal cholesterol from enhanced cholesterol secretion in liver G5/G8-Tg mice have in of ABCG5/G8 in the no changes in ABCG5/G8 or in fractional intestinal cholesterol absorption These demonstrate that overexpression of ABCG5/G8 only in liver not have on dietary cholesterol the fecal J. J. Clin. Investig. PubMed Scopus Google in fractional cholesterol absorption of mice ABCG5/G8 in liver and The decreased intestinal cholesterol in the transgenic mice of J. J. Clin. Investig. PubMed Scopus Google to to the intestinal overexpression of ABCG5/G8, as hepatic of the plasma of plant and the plasma in liver G5/G8-Tg mice. These findings that for removal of plant sterols from plasma by hepatic Hepatic ABCG5/G8 enhance the secretion of hepatic cholesterol and plant sterols into bile hepatic cholesterol by cholesterol cholesterol but not plant the plant in plasma However, in the in plasma plant sterols in liver G5/G8-Tg versus mice cholesterol in liver and plasma and cholesterol was not to we no of increased cholesterol or changes in in liver G5/G8-Tg versus mice on genetic plant sterols by the intestine and to the liver into the bile the hepatobiliary by liver ABCG5/G8, plant sterols in plasma. The increased plant in bile of liver G5/G8-Tg mice that hepatic ABCG5/G8 secretion of sterols into an for plant sterols and demonstrate that in the absence of changes in intestinal ABCG5/G8 or fractional intestinal cholesterol absorption, enhanced sterol by ABCG5/G8 in protect against the accumulation of dietary plant in plasma. that plant in to cholesterol, to in human Salen G. Metabolism. PubMed Scopus Google Thus, the accumulation of plant sterols in plasma an for liver have that in of in the receptor J. J. Clin. Investig. PubMed Scopus Google on known in sterol transport, ABCG5 and ABCG8 also to development by hepatic cholesterol changes in hepatic receptor and and plasma Thus, of that the of liver ABCG5/G8 also on the of to of cholesterol from the hepatic cholesterol by of hepatic lipoprotein in the plasma of in hepatic cholesterol in mice J. PubMed Scopus Google the of ABCG5/G8 overexpression on the plasma liver G5/G8-Tg mice of liver cholesterol ABCG5/G8 overexpression increased the of cholesterol from the liver the to the of cholesterol to the liver from the absorption and transport of intestinal cholesterol different to of liver overexpression of ABCG5/G8 fractional intestinal cholesterol absorption or changes in cholesterol demonstrate that in liver of ABCG5/G8 did not alter fractional intestinal cholesterol absorption in of the in ABCG5/G8 overexpression cholesterol secretion to of the intestinal of cholesterol that in the absence of changes in intestinal absorption, of hepatobiliary cholesterol the of liver cholesterol the bile the of cholesterol from the intestine in liver G5/G8-Tg mice hepatic cholesterol the hepatic overexpression of ABCG5/G8 did not alter hepatic cholesterol hepatic cholesterol hepatic of or alter the plasma lipid profile, including the plasma of plasma in C57Bl/6, apoE-KO, or LDLr-KO mice. These demonstrate that the of liver cholesterol the ABCG5/G8 only in liver and not intestine to of hepatic cholesterol in liver G5/G8-Tg mice and that hepatic overexpression of ABCG5/G8 not protect against the development of we in three mice on mice on an and LDLr-KO mice on of changes in the cholesterol the liver induced by hepatic ABCG5/G8 overexpression in liver G5/G8-Tg mice into the sterol transport of versus liver G5/G8-Tg mice and of LDLr-KO versus liver G5/G8-Tg LDLr-KO mice of ABCG5/G8 in liver enhanced cholesterol secretion in and LDLr-KO mice. Consequently, the amount of intestinal cholesterol available for absorption was also increased in liver G5/G8-Tg versus mice and liver G5/G8-Tg LDLr-KO versus LDLr-KO mice However, hepatic overexpression of ABCG5/G8 did not the fractional intestinal cholesterol absorption in the amount of cholesterol from the intestine was also in liver G5/G8-Tg versus and in liver G5/G8-Tg LDLr-KO versus LDLr-KO Thus, the increased hepatic cholesterol the in liver G5/G8-Tg and liver G5/G8-Tg LDLr-KO mice was by of cholesterol to the liver from absorption and transport of intestinal cholesterol Consequently, hepatic overexpression of ABCG5/G8 did not alter fecal cholesterol excretion in C57Bl/6, apoE-KO, and LDLr-KO mice. changes in bile fecal excretion in mice bile secretion was and liver G5/G8-Tg mice in genetic and have that bile not by ABCG5/G8 overexpression J. J. Clin. Investig. PubMed Scopus Google Thus, hepatic overexpression of ABCG5/G8 only in liver did not alter hepatic cholesterol enhance the of cholesterol from the body in liver G5/G8-Tg mice versus mice. demonstrate that hepatic ABCG5/G8 overexpression to cholesterol and plant sterol secretion into bile and as an alternative mechanism, independent of intestinal ABCG5/G8, to protect against the accumulation of plant sterols in plasma. However, cholesterol secretion the amount of intestinal cholesterol available for absorption, secretion of sterols in bile not by sufficient to alter hepatic cholesterol and protect against These not the that in intestinal cholesterol absorption, as in hepatic overexpression of ABCG5/G8 in findings demonstrate that overexpression of ABCG5/G8 in liver profoundly alters hepatic but not intestinal sterol transport, identifying distinct roles for liver and intestinal ABCG5/G8 in modulating sterol metabolism. for and and and for the of and fecal sterol and aortic