Jc. Rodriguez et al., PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR MEDIATES INDUCTION OF THE MITOCHONDRIAL 3-HYDROXY-3 METHYLGLUTARYL-COA SYNTHASE GENE BY FATTY-ACIDS, The Journal of biological chemistry, 269(29), 1994, pp. 18767-18772
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.