title: 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 approximately 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.
authors.affiliation: Molecular Disease Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Justina E
authors.initials: JE
authors.lastname: Wu
authors.forename: Federica
authors.initials: F
authors.lastname: Basso
authors.forename: Robert D
authors.initials: RD
authors.lastname: Shamburek
authors.forename: Marcelo J A
authors.initials: MJ
authors.lastname: Amar
authors.forename: Boris
authors.initials: B
authors.lastname: Vaisman
authors.forename: Gergely
authors.initials: G
authors.lastname: Szakacs
authors.forename: Charles
authors.initials: C
authors.lastname: Joyce
authors.forename: Terese
authors.initials: T
authors.lastname: Tansey
authors.forename: Lita
authors.initials: L
authors.lastname: Freeman
authors.forename: Beverly J
authors.initials: BJ
authors.lastname: Paigen
authors.forename: Fairwell
authors.initials: F
authors.lastname: Thomas
authors.forename: H Bryan
authors.initials: HB
authors.lastname: Brewer
authors.forename: Silvia
authors.initials: S
authors.lastname: Santamarina-Fojo
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000503:physiopathology; D001161:Arteriosclerosis / Q000378:metabolism / Q000503:physiopathology; D001659:Biliary Tract / Q000378:metabolism; D001692:Biological Transport; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004032:Diet; D005786:Gene Expression Regulation; D006801:Humans; D008074:Lipoproteins / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D013261:Sterols / Q000378:metabolism*
chemical_list: C416945:ABCG5 protein, human; C416946:ABCG8 protein, human; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D002791:Cholesterol, Dietary; D008074:Lipoproteins; D013261:Sterols