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J. Biol. Chem., Vol. 281, Issue 40, 29840-29849, October 6, 2006

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Underexpressed Coactivators PGC1 AND SRC1 Impair Hepatocyte Nuclear Factor 4 Function and Promote Dedifferentiation in Human Hepatoma Cells^*

Celia P. Martínez-Jiménez¹, M. José Gómez-Lechón, José V. Castell, and Ramiro Jover²

From the Unidad de Hepatología Experimental, Centro de Investigación, Hospital Universitario La Fe, 46009 Valencia, Spain and Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain

Hepatocyte nuclear factor 4 (HNF4) plays critical roles during liver development and in the transcriptional regulation of many hepatic genes in adult liver. Here we have demonstrated that in human hepatoma HepG2 cells, HNF4 is expressed at levels as high as in human liver but its activity on target genes is very low or absent. We have discovered that the low expression of key coactivators (PGC1, SRC1, SRC2, and PCAF) might account for the lack of function of HNF4 in HepG2 cells. Among them, PGC1 and SRC1 are the two most important HNF4 coactivators as revealed by reporter assays with an Apo-CIII promoter construct. Moreover, the expression of these two coactivators was found to be down-regulated in all human hepatomas investigated. Overexpression of SRC1 and PGC1 by recombinant adenoviruses led to a significant up-regulation of well characterized HNF4-dependent genes (ApoCIII, ApoAV, PEPCK, AldoB, OTC, and CYP7A1) and forced HepG2 cells toward a more differentiated phenotype as demonstrated by increased ureogenic rate. The positive effect of PGC1 was seen to be dependent on HNF4. Finally, insulin treatment of human hepatocytes and HepG2 cells caused repression of PGC1 and a concomitant down-regulation of ApoCIII, PEPCK, AldoB, and OTC. Altogether, our results suggest that SRC1, and notably PGC1, are key coactivators for the proper function of HNF4 in human liver and for an integrative control of multiple hepatic genes involved in metabolism and homeostasis. The down-regulation of key HNF4 coactivators could be a determinant factor for the dedifferentiation of human hepatomas.

Received for publication, April 27, 2006 , and in revised form, August 4, 2006.

^* This work was supported in part by a grant from the Ministry of Science and Technology (SAF 2003-09353) and from a European Union Integrated Research Project (PREDICTOMICS LSHB-CT-2004-504761). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3 and Tables S1 and S2.

¹ Recipient of a predoctoral grant from the Consellería de Educación Ciencia y Cultura, Generalitat Valenciana (Valencian Regional Government).

² To whom correspondence should be addressed: Unidad de Hepatología Experimental, Centro de Investigación, Hospital La Fe, Avenida de Campanar, 21, 46009 Valencia, Spain. Tel.: 34-96-197-30-48; Fax: 34-96-197-30-18; E-mail: ramiro.jover{at}uv.es.

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