Original Article

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

Correspondence to: Stefan E. H. Alexson

Long-chain acyl-CoA thioesterases catalyze the hydrolysis of acyl-CoAs to the corresponding free fatty acid and CoA. We recently cloned four members of a novel multi-gene family of peroxisome proliferator-induced genes encoding cytosolic (CTE-I), mitochondrial (MTE-I), and peroxisomal (PTE-Ia and PTE-Ib) acyl-CoA thioesterases (Hunt et al. 1999. J. Biol. Chem. 274: 34317–34326). As the peroxisome proliferator-activated receptor alpha (PPAR) plays a central role in regulating genes involved in lipid metabolism, we examined the involvement of this receptor in regulation of the thioesterases, particularly CTE-I and MTE-I. Northern blot analysis shows that the induction of these thioesterases by clofibrate is mediated through a strictly PPAR-dependent mechanism. All four acyl-CoA thioesterases are induced at mRNA level by fasting and using PPAR-null mice, it is evident that the increase in CTE-I due to fasting is mainly independent of the PPAR in liver and heart. The CTE-I gene responds rapidly to fasting, with induction 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 refeeding, and being further repressed to 20% of control after 9 h refeeding. Although CTE-I mRNA shows a low basal expression in liver, it can be suppressed 90% by feeding a fat-free diet.

These data demonstrate that the nutritional regulation of the thioesterases involves the PPAR and other signaling pathways responsible for activation and repression. Putative physiological functions for the acyl-CoA thioesterases are discussed.—Hunt, M. C., P. J. G. Lindquist, J. M. Peters, F. J. Gonzalez, U. Diczfalusy, and S. E. H. Alexson. Involvement of the peroxisome proliferator-activated receptor in regulating long-chain acyl-CoA thioesterases. J. Lipid Res. 2000. 41: 814;–823.

Supplementary key words: acyl-CoA thioesterases, acyl-CoA, fasting, peroxisome proliferator-activated receptor, lipid metabolism, fat free diet, clofibrate

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