title: Hepatic ABCG5/G8 overexpression reduces apoB-lipoproteins and atherosclerosis when cholesterol absorption is inhibited.
abstract: We previously reported that liver-specific overexpression of ABCG5/G8 in mice is not atheroprotective, suggesting that increased biliary cholesterol secretion must be coupled with decreased intestinal cholesterol absorption to increase net sterol loss from the body and reduce atherosclerosis. To evaluate this hypothesis, we fed low density lipoprotein receptor-knockout (LDLr-KO) control and ABCG5/G8-transgenic (ABCG5/G8-Tg)xLDLr-KO mice, which overexpress ABCG5/G8 only in liver, a Western diet containing ezetimibe to reduce intestinal cholesterol absorption. On this dietary regimen, liver-specific ABCG5/G8 overexpression increased hepatobiliary cholesterol concentration and secretion rates (1.5-fold and 1.9-fold, respectively), resulting in 1.6-fold increased fecal cholesterol excretion, decreased hepatic cholesterol, and increased (4.4-fold) de novo hepatic cholesterol synthesis versus LDLr-KO mice. Plasma lipids decreased (total cholesterol, 32%; cholesteryl ester, 32%; free cholesterol, 30%), mostly as a result of reduced non-high density lipoprotein-cholesterol and apolipoprotein B (apoB; 36% and 25%, respectively). ApoB-containing lipoproteins were smaller and lipid-depleted in ABCG5/G8-TgxLDLr-KO mice. Kinetic studies revealed similar 125I-apoB intermediate density lipoprotein/LDL fractional catabolic rates, but apoB production rates were decreased 37% in ABCG5/G8-TgxLDLr-KO mice. Proximal aortic atherosclerosis decreased by 52% (male) and 59% (female) in ABCG5/G8-TgxLDLr-KO versus LDLr-KO mice fed the Western/ezetimibe diet. Thus, increased biliary secretion, resulting from hepatic ABCG5/G8 overexpression, reduces atherogenic risk in LDLr-KO mice fed a Western diet containing ezetimibe. These findings identify distinct roles for liver and intestinal ABCG5/G8 in modulating sterol metabolism and atherosclerosis.
authors.affiliation: Molecular Disease Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Federica
authors.initials: F
authors.lastname: Basso
authors.forename: Lita A
authors.initials: LA
authors.lastname: Freeman
authors.forename: Carol
authors.initials: C
authors.lastname: Ko
authors.forename: Charles
authors.initials: C
authors.lastname: Joyce
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Amar
authors.forename: Robert D
authors.initials: RD
authors.lastname: Shamburek
authors.forename: Terese
authors.initials: T
authors.lastname: Tansey
authors.forename: Fairwell
authors.initials: F
authors.lastname: Thomas
authors.forename: Justina
authors.initials: J
authors.lastname: Wu
authors.forename: Beverly
authors.initials: B
authors.lastname: Paigen
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.forename: Silvia
authors.initials: S
authors.lastname: Santamarina-Fojo
authors.forename: H Bryan
authors.initials: HB
authors.lastname: Brewer
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 / Q000235:genetics*; D000818:Animals; D001055:Apolipoproteins B / Q000097:blood*; D050197:Atherosclerosis / Q000517:prevention & control*; D001646:Bile / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis / Q000493:pharmacokinetics*; D004032:Diet; D007408:Intestinal Absorption; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013261:Sterols / Q000378:metabolism
chemical_list: C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D001055:Apolipoproteins B; D008055:Lipids; D008074:Lipoproteins; D011973:Receptors, LDL; D013261:Sterols; D012313:RNA; D002784:Cholesterol