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United States Department of Agriculture

Agricultural Research Service

Title: Diabetes and activation of peroxisome proliferator activated receptor alpha increases mitochondrial thioesterase I protein expression and activity in the heart)

Author
item King, Kristen
item Young, Martin
item Kerner, Janos
item Huang, Hazel
item O'shea, Karen
item Alexson, Stefan
item Hoppel, Charles
item Stanley, William

Submitted to: Circulation
Publication Type: Abstract Only
Publication Acceptance Date: 7/20/2006
Publication Date: 10/31/2006
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.

Interpretive Summary:

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.

Last Modified: 8/24/2016
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