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J. Biol. Chem., Vol. 281, Issue 15, 10081-10088, April 14, 2006

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A Prospero-related Homeodomain Protein Is a Novel Co-regulator of Hepatocyte Nuclear Factor 4 That Regulates the Cholesterol 7-Hydroxylase Gene^*

From the Department of Microbiology, Immunology and Biochemistry, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio 44272

Prox1, an early specific marker for developing liver and pancreas in foregut endoderm has recently been shown to interact with -fetoprotein transcription factor and repress cholesterol 7-hydroxylase (CYP7A1) gene transcription. Using a yeast two-hybrid assay, we found that Prox1 strongly and specifically interacted with hepatocyte nuclear factor (HNF)4, an important transactivator of the human CYP7A1 gene in bile acid synthesis and phosphoenolpyruvate carboxykinase (PEPCK) gene in gluconeogenesis. A real time PCR assay detected Prox1 mRNA expression in human primary hepatocytes and HepG2 cells. Reporter assay, GST pull-down, co-immunoprecipitation, and yeast two-hybrid assays identified a specific interaction between the N-terminal LXXLL motif of Prox1 and the activation function 2 domain of HNF4. Prox1 strongly inhibited HNF4 and peroxisome proliferators-activated receptor coactivator-1 co-activation of the CYP7A1 and PEPCK genes. Knock down of the endogenous Prox1 by small interfering RNA resulted in significant increase of CYP7A1 and PEPCK mRNA expression and the rate of bile acid synthesis in HepG2 cells. These results suggest that Prox1 is a novel co-regulator of HNF4 that may play a key role in the regulation of bile acid synthesis and gluconeogenesis in the liver.

Received for publication, December 16, 2005 , and in revised form, February 16, 2006.

^* This work was supported by National Institutes of Health Grants DK58379 and DK44442. 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.

¹ To whom correspondence should be addressed: Dept. of Microbiology, Immunology and Biochemistry, Northeastern Ohio University College of Medicine, 4209 State Route 44, P.O. Box 95, Rootstown, OH 44272. Tel.: 330-325-6694; Fax: 330-325-5910; E-mail: jchiang{at}neoucom.edu.

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