Long-chain fatty acids regulate liver carnitine palmitoyltransferase I gene (L-CPT I) expression through a peroxisome-proliferator-activated receptor alpha (PPARalpha)-independent pathway.
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.
Louet
J F
JF
Endocrinologie Métabolisme et Développement, CNRS UPR 1524, 9, rue Jules Hetzel, 92190 Meudon, France.
Chatelain
F
F
Decaux
J F
JF
Park
E A
EA
Kohl
C
C
Pineau
T
T
Girard
J
J
Pegorier
J P
JP
D000818:Animals; D001483:Base Sequence; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics*; D002478:Cells, Cultured; D002994:Clofibrate / Q000494:pharmacology; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000502:physiology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D002334:Carnitine O-Palmitoyltransferase; D002994:Clofibrate