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J. Biol. Chem., Vol. 280, Issue 10, 8742-8747, March 11, 2005

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Expression of ABCG5 and ABCG8 Is Required for Regulation of Biliary Cholesterol Secretion^*

Liqing Yu, Sarita Gupta, Fang Xu¶, Amy D. B. Liverman||, Antonio Moschetta||, David J. Mangelsdorf||**, Joyce J. Repa, Helen H. Hobbs**, and Jonathan C. Cohen¶¶

From the McDermott Center for Human Growth and Development, Departments of Molecular Genetics, ^||Pharmacology, Internal Medicine, and Physiology, ^¶Center for Human Nutrition, and ^**Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046

The major pathway for elimination of cholesterol in mammals is via secretion into bile. Biliary cholesterol secretion is mediated by the ATP-binding cassette (ABC) transporters ABCG5 (G5) and ABCG8 (G8) and is stimulated by cholesterol and by the non-cholesterol steroids cholate and diosgenin. To define the relationship between G5G8 expression and biliary cholesterol secretion, we measured G5 and G8 mRNA levels and biliary cholesterol concentrations in genetically manipulated mice expressing 0, 1, 2, 5, 10, or 16 copies of the two genes. Biliary cholesterol levels varied directly with G5G8 copy number and hepatic mRNA levels over a >16-fold range. Thus neither delivery of cholesterol to the transporter nor levels of cholesterol acceptors in bile were limiting under these conditions. In wild-type mice, cholate and diosgenin both increased biliary cholesterol concentrations 2–3-fold. The increase in biliary cholesterol content was dependent on expression of G5 and G8; neither steroid increased biliary cholesterol levels in G5G8^–/– mice. Cholate treatment was associated with a farnesoid X receptor (FXR)-dependent increase in hepatic mRNA and protein levels of G5 and G8. In contrast to cholate, diosgenin treatment did not affect G5G8 expression. Diosgenin increased the expression of several pregnane X receptor (PXR) target genes and the choleretic effect of diosgenin was reduced by 70% in PXR knock-out mice. Thus G5 and G8 are required to modulate biliary cholesterol secretion in response to cholate and diosgenin, but the choleretic effects of these two steroids are mediated by different mechanisms requiring FXR and PXR, respectively.

Received for publication, September 27, 2004 , and in revised form, November 24, 2004.

^* This work was supported by National Institutes of Health Grants HL20948 and HL72304, the Perot Family Foundation, the W. M. Keck Foundation, and the Donald W. Reynolds Clinical Cardiovascular Research Center at Dallas. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶¶ To whom correspondence should be addressed: Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9052. Tel.: 214-648-4774; Fax: 214-648-4837; E-mail: jonathan.cohen{at}utsouthwestern.edu.

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