Mouse carnitine–acylcarnitine translocase (CACT) is transcriptionally regulated by PPARα and PPARδ in liver cells

BackgroundHepatic PPARα 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 β-oxidation of fatty acid moieties, is also regulated by PPARα in the liver has not yet been investigated.Methods and ResultsHerein, we observed that hepatic mRNA abundance of CACT was increased by both, fasting and treatment with PPARα agonist WY-14,643 in wild-type mice but not PPARα-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 PPARδ agonist GW0742, but not with PPARγ 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.General significanceCACT is upregulated by PPARα and PPARδ, probably by binding to a functional PPRE at position + 45 to + 57 relative to the transcription start site. The upregulation of CACT by PPARα and PPARδ, 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.