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The Hepatocyte Nuclear Factor 4 (HNF-4) Represses the Mitochondrial HMG-CoA Synthase Gene

https://doi.org/10.1006/bbrc.1997.8032Get rights and content

Abstract

We have recently shown that the gene for the mitochondrial HMG-CoA synthase is a target for PPAR and that this receptor mediates the induction of this gene by fatty acids. With the aim of gaining further insight into the function and regulation of this gene we examined the effect of other members of the nuclear hormone receptor superfamily on its expression. We previously identified a regulatory element in the mitochondrial HMG-CoA synthase gene promoter that confers transcriptional regulation by PPAR, RXR and the orphan nuclear receptor COUP-TF. In this study we demonstrate a trans-repressing regulatory function for HNF-4 at this same nuclear receptor response element (NRRE). HNF-4 binds to the mitochondrial HMG-CoA synthase NRRE, and, in cotransfection assays in HepG2 cells, it represses PPAR-dependent activation of a reporter gene linked to the mitochondrial HMG-CoA synthase gene promoter.These results suggest that the mitochondrial HMG-CoA synthase gene is subject to differential regulation by the interplay of multiple members of the nuclear hormone receptor superfamily.

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    The abbreviations used are: HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; CAT, chloramphenicol acetyltransferase; COUP-TF, chicken ovalbumin upstream promoter transcription factor; PPAR, peroxisome proliferator-activated receptor; PPRE, peroxisome proliferator-responsive element; NRRE, nuclear receptor-responsive element; RAR, retinoic acid receptor; TR thyroid hormone receptor; HNF-4, hepatic nuclear factor 4; hRXRα, human 9-cis-retinoic acid receptor α; mPPARα, mouse peroxisome proliferator-activated receptor α; EMSA, electrophoretic mobility shift analysis

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    Present address: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235.

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    Present address: IGBMC. CNRS INSERM. Université Louis Pasteur. C.U. de Strasbourg, France.

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    To whom correspondence should be addressed: Unitat de Bioquı́mica, Facultat de Farmàcia, Avda. Diagonal, 643, 08028 Barcelona, Spain. E-mail: [email protected].

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