PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR MEDIATES INDUCTION OF THE MITOCHONDRIAL 3-HYDROXY-3 METHYLGLUTARYL-COA SYNTHASE GENE BY FATTY-ACIDS

Fatty acids induce an increase in the transcription of the mitochondri al 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase gene, which encod es an enzyme that has been proposed as a control site of ketogenesis. We studied whether the peroxisome proliferator-activated receptor (PPA R) is involved in the mechanism of this transcriptional induction. We found that cotransfection of a rat mitochondrial HMG-CoA synthase prom oter-chloramphenicol acetyltransferase reporter plasmid and a PPAR exp ression plasmid in the presence of the peroxisome proliferator clofibr ate led to a more than 30-fold increase in chloramphenicol acetyltrans ferase activity, relative to the activity in the absence of both PPAR and inducer. Linoleic acid, a polyunsaturated fatty acid, increased th is activity as potently as does clofibrate and more effectively than d oes monounsaturated oleic acid. We have identified, by deletional anal ysis, an element located 104 base pairs upstream of the mitochondrial HMG-CoA synthase gene, which confers PPAR responsiveness to homologous and heterologous promoters. This is the first example of a peroxisome proliferator-responsive element (PPRE) in a gene encoding a mitochond rial protein. This element contains an imperfect direct repeat that is similar to those described in the PPREs of other genes. Furthermore, gel retardation and cotransfection assays revealed that, as for other genes, PPAR heterodimerizes with retinoid X receptor and that both rec eptors cooperate for binding to the mitochondrial HMG-CoA synthase PPR E and subsequent activation of the gene. In conclusion, our data demon strate that regulation of mitochondrial HMG-CoA synthase gene expressi on by fatty acids is mediated by PPAR, supporting the hypothesis that PPAR has an important role at the transcriptional level in the regulat ion of lipid metabolism.