Cloning and regulation of peroxisome proliferator-induced acyl-CoA thioesterases from mouse liver

1.1. Acyl-CoA thioesterases hydrolyze acyl-CoAs to the corresponding free fatty acid plus CoASH. The activity is strongly induced in rat and mouse liver after feeding the animals peroxisome proliferators. To elucidate the role of these enzymes in lipid metabolism, we have cloned the cDNAs corresponding to the inducible cytosolic and mitochondrial type I enzymes (CTE-I and MTE-I) and studied tissue expression and nutritional regulation of expression of the mRNAs in mice. The constitutive expression of both mRNAs was low in liver, with CTE-I being expressed mainly in kidney and brown adipose tissue and MTE-I expressed in brown adipose tissue and heart. As expected, the expression in liver of both the CTE-I and MTE-I mRNAs was strongly induced (> 50-fold) by treatment with clofibrate. A similar level of induction was observed by fasting and a time-course study showed that both mRNAs were increased already at 6 hours after removal of the diet. Refeeding normal chow diet to mice fasted for 24 hours normalized the mRNA levels with a T1/2 of about 3-4 hours. Feeding mice a fat-free diet further decreased the expression, possibly indicating repression of expression. The strong expression of MTE-I and CTE-I in the heart was increased about 10-fold by fasting. To further characterize these highly regulated enzymes, we have cloned the corresponding genes and promoter regions. The structures of the two genes were found to be very similar, consisting of three exons and two introns. Exon-intron borders conform to general consensus sequences and especially the first exon appears to be highly conserved. The promoter regions of both the CTE-I and MTE-I genes contain putative peroxisome proliferator response elements (PPREs), suggesting an involvement of peroxisome proliferator-activated receptors in the regulation of these genes.