Involvement of the peroxisome proliferator-activated receptor alpha in regulating long-chain acyl-CoA thioesterases

Long-chain acyl-CoA thioesterases catalyze the hydrolysis of acyl-CoAs to t he corresponding free fatty acid and CoA, We recently cloned four members o f a novel multigene family of peroxisome proliferator-induced genes encodin g cytosolic (CTE-I), mitochondrial (MTE-I), and peroxisomal (PTE-Ia and PTE -Ib) acyl-CoA thioesterases (Hunt ct al. 1999, J. Biol. Chem. 274: 34317-34 326), As the peroxisome proliferator-activated receptor alpha (PPAR alpha) plays a central role in regulating genes involved in lipid metabolism, we e xamined the involvement of this receptor in regulation of the thioesterases , particularly CTE-I and MTE-I. Northern blot analysis shows that the induc tion of these thioesterases by clofibrate is mediated through a strictly PP AR alpha-dependent mechanism. All four acyl-CoA thioesterases are induced a t mRNA level by fasting and using PPAR alpha-null mice, it is evident that the increase in CTEI due to fasting is mainly independent of the PPAR alpha in liver and heart. The CTEI gene responds rapidly to fasting, with induct ion of mRNA and protein evident after 6 h. This: fasting effect is rapidly reversible, with CTE-I mRNA returning almost to control levels after 3 h re feeding, and being further repressed to 20% of control after 9 h refeeding. Although CTEI mRNA shows a low basal expression in liver, it can be suppre ssed 90% by feeding a fat-free diet. These data demonstrate that the nutrit ional regulation of the thioesterases involves the PPAR alpha and other sig naling pathways responsible for activation and repression, Putative physiol ogical functions for the acyl-CoA thioesterases are discussed. Involvement of the peroxisome proliferator-activated receptor alpha in regulating long- chain acyl-CoA thioesterases.