Abstract 1296: Diabetes and Activation of Peroxisome Proliferator Activated Receptor α Increases Mitochondrial Thioesterase I Protein Expression and Activity in the Heart
Mitochondrial thioesterase-I (MTE-I) catalyzes the de-esterification of fattyacyl-CoAs to fatty acid anions in the mitochondrial matrix, which are extruded to the cytosol, thus preventing the accumulation of toxic mitochondrial fattyacyl-CoAs. MTE-I mRNA expression in the heart is regulated by peroxisome proliferator activator receptor β (PPARβ). Diabetes also increases MTE-I mRNA, presumably through greater fatty acid activation of PPARβ. MTE-I protein expression and activity have not been reported in cardiac mitochondria. We hypothesized that MTE-I protein expression and activity are increased in diabetes, and that this effect can be mimicked by a PPARβ agonist. Subsarcolemmal (SSM) and intrafibrillar (IFM) mitochondria were isolated from rats that were either untreated, streptozotocin diabetic (10–14 days), or treated with the PPARα agonist fenofibrate (300mg/kg/day for 4 wks) (n±8 –12/group). Diabetes increased plasma free fatty acids 14-fold, cardiac MTE-I mRNA 7-fold, and MTE-I protein expression and activity in isolated mitochondria (see table⇓). These effects on MTE-I mRNA levels, along with mitochondrial protein expression and activity, were mimicked by PPARα activation with fenofibrate. The protein expression of uncoupling protein 3 (UCP3), which is located on the inner mitochondrial membrane and thought to transport MTE-I generated fatty acid anions out the mitochondrial membrane, was also measured in isolated SSM and IFM. UCP3 was not signficantly affected by either diabetes or fenofibrate despite a>4-fold increase in UCP3 mRNA.
Conclusion: Diabetes increases MTE-I protein expression and activity in cardiac mitochondria. This effect is likely mediated by fatty acid activation of PPARα, and may reduce cardiac lipotoxicity in diabetes. *p±0.001 vs control