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J. Biol. Chem., Vol. 279, Issue 4, 2480-2489, January 23, 2004

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Hepatocyte Nuclear Factor 4 Is a Central Regulator of Bile Acid Conjugation^*

Yusuke Inoue, Ai-Ming Yu, Junko Inoue, and Frank J. Gonzalez

From the Laboratory of Metabolism, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892

Hepatocyte nuclear factor 4 (HNF4) has an important role in regulating the expression of liver-specific genes. Because bile acids are produced from cholesterol in liver and many enzymes involved in their biosynthesis are preferentially expressed in liver, the role of HNF4 in the regulation of bile acid production was examined. In mice, unconjugated bile acids are conjugated with taurine by the liver-specific enzymes, bile acid-CoA ligase and bile acid-CoA:amino acid N-acyltransferase (BAT). Mice lacking hepatic HNF4 expression exhibited markedly decreased expression of the very long chain acyl-CoA synthase-related gene (VLACSR), a mouse candidate for bile acid-CoA ligase, and BAT. This was associated with markedly elevated levels of unconjugated and glycine-conjugated bile acids in gallbladder. HNF4 was found to bind directly to the mouse VLACSR and BAT gene promoters, and the promoter activities were dependent on HNF4-binding sites and HNF4 expression. In conclusion, HNF4 plays a central role in bile acid conjugation by direct regulation of VLACSR and BAT in vivo.

Received for publication, October 7, 2003 , and in revised form, October 24, 2003.

^* 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: Laboratory of Metabolism, Center for Cancer Research, NCI, National Institutes of Health, 9000 Rockville Pike, Bldg. 37, Rm. 3106, Bethesda, MD 20892. Tel.: 301-496-9067; Fax: 301-496-8419; E-mail: fjgonz{at}helix.nih.gov.

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