Thioesterase activity and acyl-CoA/fatty acid cross talk of hepatocyte nuclear factor-4alpha

doi:10.1074/jbc.M500732200

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Papers In Press, published online ahead of print May 3, 2005
J. Biol. Chem, 10.1074/jbc.M500732200
Submitted on January 20, 2005
Revised on May 2, 2005
Accepted on May 3, 2005

Thioesterase activity and acyl-CoA/fatty acid cross talk of hepatocyte nuclear factor-4 $alpha$

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

Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem 91120

Corresponding Author: bartanaj{at}cc.huji.ac.il

Hepatocyte nuclear factor-4 $alpha$ (HNF-4 $alpha$ ) activity is modulated by natural and xenobiotic fatty acid and fatty acyl-CoA ligands as function of their chain length, unsaturation and substitutions. The acyl-CoA site of HNF-4 $alpha$ 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 $alpha$ 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 $alpha$ thioesterase may exchange with free acids entrapped in the fatty acid pocket of HNF-4 $alpha$ . Cross talk between the acyl-CoA and free fatty acid binding sites is abrogated by high affinity, nonhydrolysable acyl-CoA ligands of HNF-4 $alpha$ that inhibit its thioesterase activity. Hence, HNF-4 $alpha$ 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 $alpha$ extends the paradigm of nuclear receptors .

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