THE HEPATOCYTE NUCLEAR FACTOR-4 (HNF-4) REPRESSES THE MITOCHONDRIAL HMG-COA SYNTHASE GENE

We have recently shown that the gene for the mitochondrial HMG-CoA syn thase is a target for PPAR and that this receptor mediates the inducti on of this gene by fatty acids. With the aim of gaining further insigh t into the function and regulation of this gene we examined the effect of other members of the nuclear hormone receptor superfamily on its e xpression. We previously identified a regulatory element in the mitoch ondrial HMG-CoA synthase gene promoter that confers transcriptional re gulation 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 assay s in HepG2 cells, it represses PPAR-dependent activation of a reporter gene linked to the mitochondrial HMG-CoA synthase gene promoter. Thes e results suggest that the mitochondrial HMG-CoA synthase gene is subj ect to differential regulation by the interplay of multiple members of the nuclear hormone receptor superfamily. (C) 1998 Academic Press.