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Journal of Lipid Research, Vol. 48, 114-126, January 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Hepatic ABCG5/G8 overexpression reduces apoB-lipoproteins and atherosclerosis when cholesterol absorption is inhibited

Federica Basso^*, Lita A. Freeman^1,*, Carol Ko^*, Charles Joyce^*, Marcelo J. Amar^*, Robert D. Shamburek^*, Terese Tansey^*, Fairwell Thomas^*, Justina Wu^*, Beverly Paigen, Alan T. Remaley^*, Silvia Santamarina-Fojo^* and H. Bryan Brewer, Jr.

^* Molecular Disease Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Jackson Laboratory, Bar Harbor, ME
Cardiovascular Research Institute, Washington Hospital Center, Washington, DC

Published, JLR Papers in Press, October 23, 2006.

¹ To whom correspondence should be addressed. e-mail: litaf{at}mail.nih.gov

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.

Supplementary key words ABC transporters • ABCG subfamily • ezetimibe • non-HDL-cholesterol • biliary sterol secretion • hepatic cholesterol homeostasis • ApoB Kinetics

Abbreviations: ABCG5/G8-Tg, ABCG5/G8-transgenic; apoB, apolipoprotein B; apoB-Lp, apolipoprotein B-containing lipoprotein; apoE-KO, apolipoprotein E-knockout; CE, cholesteryl ester; FC, free cholesterol; FCR, fractional catabolic rate; FPLC, fast-protein liquid chromatography; HDL-C, high density lipoprotein-cholesterol; IDL, intermediate density lipoprotein; LDLr-KO, low density lipoprotein receptor-knockout; LRP, LDL receptor-related protein; NPC1L1, Niemann-Pick C1-Like 1; TC, total cholesterol; TG, triglyceride

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