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J. Biol. Chem., Vol. 280, Issue 36, 31792-31800, September 9, 2005

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-Crystallin Is a Target Gene of the Farnesoid X-activated Receptor in Human Livers^*

Florence Y. Lee, Heidi R. Kast-Woelbern, Jenny Chang, Guizhen Luo¶, Stacey A. Jones¶, Michael C. Fishbein||, and Peter A. Edwards**

From the Department of Biological Chemistry and ^||Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA and the ^**Molecular Biology Institute, UCLA, Los Angeles, California 90095 and ^¶GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709

-Crystallins comprise 35% of soluble proteins in the ocular lens and possess chaperone-like functions. Furthermore, the A subunit (A-crystallin) of crystallin is thought to be "lens-specific" as only very low levels of expression were detected in a few non-lenticular tissues. Here we report that human A-crystallin is expressed in human livers and is regulated by farnesoid X-activated receptor (FXR) in response to FXR agonists. A-Crystallin was identified in a microarray screen as one of the most highly induced genes after treatment of HepG2 cells with the synthetic FXR ligand GW4064. Northern blot and quantitative real-time PCR analyses confirmed that A-crystallin expression was induced in HepG2-derived cell lines and human primary hepatocytes and hepatic stellate cells in response to either natural or synthetic FXR ligands. Transient transfection studies and electrophoretic mobility shift assays revealed a functional FXR response element located in intron 1 of the human A-crystallin gene. Importantly, immunohistochemical staining of human liver sections showed increased A-crystallin expression in cholangiocytes and hepatocytes. As a member of the small heat shock protein family possessing chaperone-like activity, A-crystallin may be involved in protection of hepatocytes from the toxic effects of high concentrations of bile acids, as would occur in disease states such as cholestasis.

Received for publication, March 23, 2005 , and in revised form, July 11, 2005.

^* This work is supported by National Institutes of Health Grants HL30568 and HL68445 (to P. A. E.), a grant from the Laubisch Fund (to P. A. E), and United States Public Health Service National Research Service Award GM07185 (to F. Y. 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.

Present address: Ligand Pharmaceuticals, 10275 Science Center Drive, San Diego, CA 92121.

To whom correspondence should be addressed: Dept. of Biological Chemistry, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, 33-257 CHS, Los Angeles, CA 90095. Tel.: 310-206-3717; Fax: 310-794-7345; E-mail: pedwards{at}mednet.ucla.edu.

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