J. Lipid Res.
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A more recent version of this article appeared on August 1, 2004

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J. Lipid Res., doi:10.1194/jlr.M400167-JLR200
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Submitted on April 29, 2004
Revised on May 27, 2004
Accepted on May 27, 2004

High-level expression of ABCG5 and ABCG8 attenuates diet-induced hypercholesterolemia and atherosclerosis in Ldlr-/-mice

Kenneth R. Wilund, Liqing Yu, Fang Xu, Helen H. Hobbs, and Jonathan C. Cohen

UT Southwestern Medical Center, Dallas, TX 75390-9052

Corresponding Author: jonathan.cohen{at}utsouthwestern.edu

Transgenic mice expressing human ABCG5 (G5) and ABCG8 (G8) have decreased fractional absorption and increased biliary secretion of cholesterol, but their plasma cholesterol levels are unchanged (males) or modestly reduced (females). To determine if increased expression of G5 and G8 can ameliorate hypercholesterolemia in mice lacking low density lipoprotein receptors (LDLR), we examined the effects of G5G8 transgene expression on cholesterol metabolism and atherosclerosis in Ldlr-/- mice. In chow-fed Ldlr-/- mice the G5G8 transgene reduced fractional absorption of dietary cholesterol by 50% and increased biliary cholesterol levels by 60% but did not affect plasma cholesterol levels. On a Western diet (21% fat, 0.2% cholesterol), G5G8Tg;Ldlr-/- mice had a 30% reduction in the level of hepatic cholesterol and 45% lower plasma cholesterol levels than the Ldlr-/- mice. After 6 months on the Western diet the atherosclerotic lesion area in the aortic root and arch was ~70% lower in the G5G8Tg;Ldlr-/- than the Ldlr-/- mice and was correlated with the plasma cholesterol levels. These results demonstrate that increased expression of G5 and G8 attenuates diet-induced hypercholesterolemia in the Ldlr-/- mice, resulting in a significant reduction in plasma levels of cholesterol and aortic atherosclerotic lesion area.


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