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J. Biol. Chem., Vol. 282, Issue 19, 14437-14446, May 11, 2007

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HNF1 Inactivation Promotes Lipogenesis in Human Hepatocellular Adenoma Independently of SREBP-1 and Carbohydrate-response Element-binding Protein (ChREBP) Activation^*

Sandra Rebouissou¹, Sandrine Imbeaud^¶, Charles Balabaud^||**, Virginie Boulanger^¶, Justine Bertrand-Michel, François Tercé, Charles Auffray^¶, Paulette Bioulac-Sage^||, and Jessica Zucman-Rossi²

From the INSERM, U674, Génomique fonctionnelle des tumeurs solides, 75010 Paris Cedex, France, the Université Paris 7 Denis Diderot, Institut Universitaire d'Hématologie, Centre d'É_tude du Polymorphisme Humain (CEPH), 75010 Paris Cedex, France, the ^¶Array s/IMAGE, Genexpress, Functional Genomics and Systems Biology for Health - UMR 7091, CNRS, Université Paris 6 Pierre et Marie Curie, 94800 Villejuif, France, the ^||INSERM, U889, 33076 Bordeaux, France, Université Victor Segalen Bordeaux 2, IFR66, 33076 Bordeaux, France, the ^**Centre Hospitalier Universitaire (CHU) de Bordeaux, Hôpital Saint-André, Service d'Hépatologie, 33076 Bordeaux, France, the CHU Bordeaux, Hôpital Pellegrin, 33076 Bordeaux Cedex, and the Lipidomic Platform, INSERM, IFR30, Génopole Toulouse, CHU Purpan, 31052 Toulouse Cedex, France

Biallelic inactivating mutations of the transcription factor 1 gene (TCF1), encoding hepatocyte nuclear factor 1 (HNF1) were identified in 50% of hepatocellular adenomas (HCA) phenotypically characterized by a striking steatosis. To understand the molecular basis of this aberrant lipid storage, we performed a microarray transcriptome analysis validated by quantitative reverse transcription-PCR, Western blotting, and lipid profiling. In mutated HCA, we showed a repression of gluconeogenesis coordinated with an activation of glycolysis, citrate shuttle, and fatty acid synthesis predicting elevated rates of lipogenesis. Moreover, the strong down-regulation of liver fatty acid-binding protein suggests that impaired fatty acid trafficking may also contribute to the fatty phenotype. In addition, transcriptional profile analysis of the observed deregulated genes in non-HNF1-mutated HCA as well as in non-tumor livers allowed us to define a specific signature of the HNF1-mutated HCA. In these tumors, lipid composition was dramatically modified according to the transcriptional deregulations identified in the fatty acid synthetic pathway. Surprisingly, lipogenesis activation did not operate through sterol regulatory element-binding protein-1 (SREBP-1) and carbohydrate-response element-binding protein (ChREBP) that were repressed. We conclude that steatosis in HNF1-mutated HCA results mainly from an aberrant promotion of lipogenesis that is linked to HNF1 inactivation and that is independent of both SREBP-1 and ChREBP activation. Finally, our findings have potential clinical implications since lipogenesis can be efficiently inhibited by targeted therapies.

Received for publication, November 20, 2006 , and in revised form, March 5, 2007.

^* This work was supported by a grant from the INSERM (Réseau de Recherche clinique et en santé des populations), Association pour la Recherche sur le cancer (ARC) number 5188, Societé Nationale Française de Gastro Entérologie (SNFGE), and the Fondation de France. 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 experimental procedures, a table, and four figures.

¹ Supported by a Ligue Nationale Contre le Cancer doctoral fellowship.

² To whom correspondence should be addressed: INSERM, U674, Institut Universitaire d'Hématologie, CEPH, 27 rue Juliette Dodu, 75010 Paris, France. Tel.: 33-1-53-72-51-66; Fax: 33-1-53-72-51-58; E-mail: zucman{at}cephb.fr.

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