Hepatic ABCG5/G8 overexpression increases biliary cholesterol secretion and reduces apoB-containing lipoproteins and atherosclerosis when cholesterol absorption is inhibited by Ezetimibe

Federica Basso, Lita A. Freeman, 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

NHLBI, NIH, Bethesda, MD 20892-1666

Corresponding Author: litaf{at}mail.nih.gov

We have 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 LDLr-KO control and ABCG5/G8-TgxLDLr-KO mice, which overexpress ABCG5/G8 only in liver, a Western diet with Ezetimibe, which reduced intestinal cholesterol absorption to 5%. On this dietary regimen, liver-specific overexpression of ABCG5/G8 in LDLr-KO mice increased hepatobiliary cholesterol concentration and secretion rates (1.5-fold and 1.9-fold, respectively) vs. LDLr-KO mice, resulting in a 1.6-fold increased fecal cholesterol excretion, decreased hepatic cholesterol, upregulation of HMGCoA reductase and increased (4.4-fold) de novo hepatic cholesterol synthesis. Plasma lipids decreased (TC 32%, CE 32%, FC 30%), mostly due to reduced non-HDL-C and apoB (36% and 25%). ApoB-containing lipoproteins were smaller and lipid-depleted in ABCG5/G8-TgxLDLr-KO mice. Kinetic studies revealed similar 125I-apoB IDL/LDL FCRs but apoB production rates were 37% decreased in ABCG5/G8-TgxLDLr-KO mice. Proximal aortic atherosclerosis decreased by 52% in males and by 59% in female ABCG5/G8-TgxLDLr-KO vs. LDLr-KO mice fed a Western diet plus Ezetimibe. Thus, increased biliary secretion, resulting from hepatic ABCG5/G8 overexpression, reduces atherogenic risk in LDLr-KO mice fed a Western diet containing Ezetimibe to decrease intestinal absorption. These findings identify distinct roles for liver and intestinal ABCG5/G8 in modulating sterol metabolism and atherosclerosis.

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