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Molecular and Cellular Biology, June 2000, p. 4436-4444, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Hepatocyte-Specific Mutation Establishes Retinoid X Receptor alpha  as a Heterodimeric Integrator of Multiple Physiological Processes in the Liver

Yu-Jui Yvonne Wan,1 Dahsing An,2,3 Yan Cai,1 Joyce J. Repa,4 Tim Hung-Po Chen,2,3 Monica Flores,3 Catherine Postic,5 Mark A. Magnuson,5 Ju Chen,6 Kenneth R. Chien,6 Samuel French,1 David J. Mangelsdorf,4 and Henry M. Sucov2,3,7,*

Department of Pathology, Harbor-UCLA Medical Center, Torrance,1 Departments of Biochemistry & Molecular Biology2 and Cell & Neurobiology,7 Institute for Genetic Medicine,3 Keck School of Medicine, University of Southern California, Los Angeles, and Department of Medicine, Center for Molecular Genetics, and American Heart Association-Bugher Foundation Center for Molecular Biology, University of California, San Diego,6 California; Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas4; and Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee5

Received 13 January 2000/Returned for modification 6 March 2000/Accepted 22 March 2000

A large number of physiological processes in the adult liver are regulated by nuclear receptors that require heterodimerization with retinoid X receptors (RXRs). In this study, we have used cre-mediated recombination to disrupt the mouse RXRalpha gene specifically in hepatocytes. Although such mice are viable, molecular and biochemical parameters indicate that every one of the examined metabolic pathways in the liver (mediated by RXR heterodimerization with PPARalpha , CARbeta , PXR, LXR, and FXR) is compromised in the absence of RXRalpha . These data demonstrate the presence of a complex circuitry in which RXRalpha is integrated into a number of diverse physiological pathways as a common regulatory component of cholesterol, fatty acid, bile acid, steroid, and xenobiotic metabolism and homeostasis.

* Corresponding author. Mailing address: 2250 Alcazar St., IGM240, Los Angeles, CA 90033. Phone: (323) 442-2563. Fax: (323) 442-2764. E-mail: sucov{at}hsc.usc.edu.

Molecular and Cellular Biology, June 2000, p. 4436-4444, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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