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

• Published in: Biochemical journal Vol. 354; no. Pt 1; pp. 189 - 197
• Main Authors: Louet, J F, Chatelain, F, Decaux, J F, Park, E A, Kohl, C, Pineau, T, Girard, J, Pegorier, J P
• Format: Journal Article
• Language: English
• Published: England Portland Press 15-02-2001
• Subjects: Animals; Base Sequence; Biochemistry, Molecular Biology; Carnitine O-Palmitoyltransferase - genetics; Cells, Cultured; Clofibrate - pharmacology; DNA Primers; Enzyme Inhibitors - pharmacology; Fatty Acids - physiology; Female; Gene Expression Regulation, Enzymologic - physiology; Hepatocytes - drug effects; Hepatocytes - metabolism; Life Sciences; Liver - enzymology; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular biology; Promoter Regions, Genetic; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - physiology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transcription Factors - genetics; Transcription Factors - physiology; Tumor Cells, Cultured
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/0264-6021:3540189

Liver carnitine palmitoyltransferase I (L-CPT I) catalyses the transfer of long-chain fatty acid (LCFA) for translocation across the mitochondrial membrane. Expression of the L-CPT I gene is induced by LCFAs as well as by lipid-lowering compounds such as clofibrate. Previous studies have suggested that the peroxisome-proliferator-activated receptor alpha (PPARalpha) is a common mediator of the transcriptional effects of LCFA and clofibrate. We found that free LCFAs rather than acyl-CoA esters 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 PPARalpha-null mice. These results suggest that the PPARalpha-knockout mouse does not represent a suitable model for the regulation of L-CPT I gene expression by LCFAs in the liver. Finally, we determined that clofibrate stimulates L-CPT I through a classical direct repeat 1 (DR1) motif in the promoter of the L-CPT I gene while LCFAs induce L-CPT I via elements in the first intron of the gene. Our results demonstrate that LCFAs can regulate gene expression through PPARalpha-independent pathways and suggest that the regulation of gene expression by dietary lipids is more complex than previously proposed.