J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M500124-JLR200 on June 1, 2005

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Journal of Lipid Research, Vol. 46, 1739-1744, August 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Ezetimibe normalizes metabolic defects in mice lacking ABCG5 and ABCG8

Liqing Yu1,*, Klaus von Bergmann{dagger}, Dieter Lütjohann{dagger}, Helen H. Hobbs*,§,**,{dagger}{dagger} and Jonathan C. Cohen2,*,§,**,§§

* Departments of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390
§ Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390
** McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390
{dagger}{dagger} Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390
§§ Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390
{dagger} Department of Clinical Pharmacology, University of Bonn, D-53105 Bonn, Germany

Published, JLR Papers in Press, June 1, 2005. DOI 10.1194/jlr.M500124-JLR200

1 Present address of L. Yu: Department of Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040.

2 To whom correspondence should be addressed. e-mail: jonathan.cohen{at}utsouthwestern.edu

The ATP binding cassette transporters ABCG5 (G5) and ABCG8 (G8) limit the accumulation of neutral sterols by restricting sterol uptake from the intestine and promoting sterol excretion into bile. Humans and mice lacking G5 and G8 (G5G8–/–) accumulate plant sterols in the blood and tissues. However, despite impaired biliary cholesterol secretion, plasma and liver cholesterol levels are lower in G5G8–/– mice than in wild-type littermates. To determine whether the observed changes in hepatic sterol metabolism were a direct result of decreased biliary sterol secretion or a metabolic consequence of the accumulation of dietary noncholesterol sterols, we treated G5G8–/– mice with ezetimibe, a drug that reduces the absorption of both plant- and animal-derived sterols. Ezetimibe feeding for 1 month sharply decreased sterol absorption and plasma levels of sitosterol and campesterol but increased cholesterol in both the plasma (from 60.4 to 75.2 mg/dl) and the liver (from 1.1 to 1.87 mg/g) of the ezetimibe-treated G5G8–/– mice. Paradoxically, the increase in hepatic cholesterol was associated with an increase in mRNA levels of HMG-CoA reductase and synthase.

Together, these results indicate that pharmacological blockade of sterol absorption can ameliorate the deleterious metabolic effects of plant sterols even in the absence of G5 and G8.

Supplementary key words ATP binding cassette transporter G5 • ATP binding cassette transporter G8 • sitosterolemia • cholesterol • bile


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