Mouse carnitine-acylcarnitine translocase (CACT) is transcriptionally regulated by PPARalpha and PPARdelta in liver cells.
BACKGROUND
Hepatic PPARalpha acts as the primary mediator of the adaptive response to fasting by upregulation of a number of genes involved in fatty acid catabolism. Whether carnitine-acylcarnitine translocase (CACT), which mediates the import of acylcarnitines into the mitochondrial matrix for subsequent beta-oxidation of fatty acid moieties, is also regulated by PPARalpha in the liver has not yet been investigated.


RESULTS
Herein, we observed that hepatic mRNA abundance of CACT was increased by both, fasting and treatment with PPARalpha agonist WY-14,643 in wild-type mice but not PPARalpha-knockout mice (P<0.05). Cell culture experiments revealed that CACT mRNA abundance was higher in liver cells treated with either WY-14,643 or PPARdelta agonist GW0742, but not with PPARgamma agonist troglitazone (TGZ) than in control cells (P<0.05). In addition, reporter assays revealed activation of mouse CACT promoter by WY-14,643 and GW0742, but not TGZ. Moreover, deletion and mutation analyses of CACT promoter and 5'-UTR revealed one functional PPRE in the 5'-UTR of mouse CACT.


CONCLUSIONS
CACT is upregulated by PPARalpha and PPARdelta, probably by binding to a functional PPRE at position +45 to +57 relative to the transcription start site. The upregulation of CACT by PPARalpha and PPARdelta, which are both important for the regulation of fatty acid oxidation in tissues during fasting, may increase the import of acylcarnitine into the mitochondrial matrix during fasting.
Gutgesell
Anke
A
Institute of Agricultural and Nutritional Sciences, Martin-Luther-Universität Halle-Wittenberg, Von-Danckelmann-Platz 2, 06120 Halle, Saale, Germany.
Wen
Gaiping
G
König
Bettina
B
Koch
Alexander
A
Spielmann
Julia
J
Stangl
Gabriele I
GI
Eder
Klaus
K
Ringseis
Robert
R
D000818:Animals; D001483:Base Sequence; D001835:Body Weight / Q000187:drug effects; D002333:Carnitine Acyltransferases / Q000235:genetics* / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005215:Fasting; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D010636:Phenols; D013438:Sulfhydryl Compounds
D002333:Carnitine Acyltransferases; D002334:Carnitine O-Palmitoyltransferase; D003577:Cytochrome P-450 Enzyme System; D008156:Luciferases; D047493:PPAR alpha; D047494:PPAR delta; D011743:Pyrimidines; D013844:Thiazoles; C512110:Cyp4a10 protein, mouse; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C006253:pirinixic acid