ARS | Publication request: Diabetes and activation of peroxisome proliferator activated receptor alpha increases mitochondrial thioesterase I protein expression and activity in the heart

Submitted to: Circulation
Publication Type: Abstract Only
Publication Acceptance Date: July 20, 2006
Publication Date: October 31, 2006
Citation: King, K.L., Young, M.E., Kerner, J., Huang, H., O'Shea, K.M., Alexson, S.E., Hoppel, C.L., Stanley, W.C. 2006. Diabetes and activation of peroxisome proliferator activated receptor alpha increasesmotochondrial thioesterase I protein expression and activity in the heart [abstract]. Circulation. 114(18):245.

Technical Abstract: 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 alpha (PPARalpha). Diabetes also increases MTE-I mRNA, presumably through greater fatty acid activation of PPARalpha. 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 PPARalpha agonist. Subsarcolemmal (SSM) and intrafibrillar (IFM) mitochondria were isolated from rats that were either untreated, streptozotocin diabetic (10-14 days), or treated with the PPARalpha 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. These effects on MTE-I mRNA levels, along with mitochondrial protein expression and activity, were mimicked by PPARalpha 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 PPARalpha, and may reduce cardiac lipotoxicity in diabetes.