Long-chain fatty acids regulate liver carnitine palmitoyltransferase I gene (L-CPT I) expression through a peroxisome-proliferator-activated receptoralpha (PPAR alpha)-independent pathway

Liver carnitine palmitoyltransferase I (L-CPT I) catalyses the transfer of long-chain fatty acid (LCFA) for translocation across the mitochondrial mem brane. Expression of the L-CPT I gene is induced by LCFAs as well as by lip id-lowering compounds such as clofibrate, Previous studies have suggested t hat the peroxisome-proliferator-activated receptor alpha (PPAR alpha) is a common mediator of the transcriptional effects of LCFA and clofibrate, We f ound that free LCFAs rather than acyl-CoA eaters are the signal metabolites responsible for the stimulation of L-CPT I gene expression. Using primary culture of hepatocytes we found that LCFAs failed to stimulate L-CPT I gene expression both in wild-type and PPAR alpha -null mice. These results sugg est that the PPAR alpha -knockout mouse does not represent a suitable model for the regulation of L-CPT I gene expression by LCFAs in the liver. Final ly, we determined that clofibrate stimulates L-CPT I through a classical di rect repeat 1 (DR1) motif in the promoter of the L-CPT I gene while LCFAs i nduce L-CPT I via elements in the first intron of the gene, Our results dem onstrate that LCFAs can regulate gene expression through PPAR alpha -indepe ndent pathways and suggest that the regulation of gene expression by dietar y lipids is more complex than previously proposed.