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J. Biol. Chem., Vol. 280, Issue 26, 24451-24461, July 1, 2005

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Thioesterase Activity and Acyl-CoA/Fatty Acid Cross-talk of Hepatocyte Nuclear Factor-4^*

Rachel Hertz, Bella Kalderon, Tamara Byk, Ina Berman, Ghadeer Za'tara, Raphael Mayer, and Jacob Bar-Tana¶

From the Department of Human Nutrition and Metabolism, Hebrew University Medical School, Ein-Kerem, P. O. Box 12272, Jerusalem 91120 and Quark Biotech Inc., Weizmann Science Park, Ness Ziona 70400, Israel

Hepatocyte nuclear factor-4 (HNF-4) activity is modulated by natural and xenobiotic fatty acid and fatty acyl-CoA ligands as a function of their chain length, unsaturation, and substitutions. The acyl-CoA site of HNF-4 is reported here to consist of the E-F domain, to bind long-chain acyl-CoAs but not the respective free acids, and to catalyze the hydrolysis of bound fatty acyl-CoAs. The free acid pocket, previously reported in the x-ray structure of HNF-4 E-domain, entraps fatty acids but excludes acyl-CoAs. The acyl-CoA and free acid sites are distinctive and noncongruent. Free fatty acid products of HNF-4 thioesterase may exchange with free acids entrapped in the fatty acid pocket of HNF-4. Cross-talk between the acyl-CoA and free fatty acid binding sites is abrogated by high affinity, nonhydrolyzable acyl-CoA ligands of HNF-4 that inhibit its thioesterase activity. Hence, HNF-4 transcriptional activity is controlled by its two interrelated acyl ligands and two binding sites interphased in tandem by the thioesterase activity. The acyl-CoA/free-acid and receptor/enzyme duality of HNF-4 extends the paradigm of nuclear receptors.

Received for publication, January 20, 2005 , and in revised form, May 2, 2005.

^* This work was supported in part by the US-Israeli Binational Science Foundation. 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: Dept. of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem 91120, Israel. Tel.: 972-2-675-8305; Fax: 972-2-643-1105; E-mail: bartanaj{at}cc.huji.ac.il.

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