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J. Biol. Chem., Vol. 279, Issue 4, 2790-2799, January 23, 2004

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Hepatic Overexpression of Murine Abcb11 Increases Hepatobiliary Lipid Secretion and Reduces Hepatic Steatosis^*

Anne Figge, Frank Lammert, Beverly Paigen, Anne Henkel¶, Siegfried Matern, Ron Korstanje, Benjamin L. Shneider||, Frank Chen||, Erik Stoltenberg¶, Kathryn Spatz¶, Farzana Hoda¶, David E. Cohen**, and Richard M. Green¶

From the Department of Medicine III, University Hospital Aachen, Aachen University, 52074 Aachen, Germany, The Jackson Laboratory, Bar Harbor, Maine 04609, ^||Mount Sinai School of Medicine, New York, New York, ^**Albert Einstein College of Medicine, Bronx, New York 10461, Chicago Veterans Affairs Medical Center-Lakeside Division and ^¶Division of Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611

Abcb11 encodes for the liver bile salt export pump, which is rate-limiting for hepatobiliary bile salt secretion. We employed transthyretin-Abcb11 and BAC-Abcb11 transgenes to develop mice overexpressing the bile salt export pump in the liver. The mice manifest increases in bile flow and biliary secretion of bile salts, phosphatidylcholine, and cholesterol. Hepatic gene expression of cholesterol 7-hydroxylase and ileal expression of the apical sodium bile salt transporter are markedly reduced, whereas gene expression of targets of the nuclear bile salt receptor FXR (ileal lipid-binding protein, short heterodimer partner (SHP) is increased. Because these changes in gene expression are associated with an increased overall hydrophobicity of the bile salt pool and a 4-fold increase of the FXR ligand taurodeoxycholate, they reflect bile salt-mediated regulation of FXR and SHP target genes. Despite the increased biliary secretion of bile salts, fecal bile salt excretion is unchanged, suggestive of an enhanced enterohepatic cycling of bile salts. Abcb11 transgenic mice fed a lithogenic (high cholesterol/fat/cholic acid) diet display markedly reduced hepatic steatosis compared with wild-type controls. We conclude that mice overexpressing Abcb11 display an increase in biliary bile salt secretion and taurodeoxycholate content, which is associated with FXR/SHP-mediated changes in hepatic and ileal gene expression. Because these mice are resistant to hepatic lipid accumulation, regulation of Abcb11 may be important for the pathogenesis and treatment of steatohepatitis.

Received for publication, July 9, 2003 , and in revised form, October 16, 2003.

^* This work was supported by National Institutes of Health Grants R01 DK59580, R01 HD40027, a Veterans Affairs Merit Review Award (to R. M. G.), a grant from the Ministry of Education, Science and Research of North-Rhine-Westphalia (Germany), The Jackson Laboratory Institutional Grant CA 34196, and National Institutes of Health Grants DK48873 and DK56626 (to D. E. C.) and the Trans-NIH Bae Sequencing Program (to F. L.). 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: Northwestern University, The Feinberg School of Medicine, Searle 10-555, 303 East Chicago Ave., Chicago, IL 60611. Tel.: 312-503-1812; Fax: 312-908-6192; E-mail: r-green2{at}northwestern.edu.

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