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Papers In Press, published online ahead of print April 16, 2007
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Division of Cardiology, Dept of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201
Corresponding Author: wstanley{at}medicine.umaryland.edu
Peroxisome proliferator activator receptor a (PPARa) is a transcriptional regulator of the expression of mitochondrial thioesterase I (MTE-I) and uncoupling protein 3 (UCP3), which are induced in the heart at the mRNA level in response to diabetes. Little is known about the regulation of protein expression of MTE-I and UCP3, or MTE-I activity, thus we investigated the effects of diabetes and treatment with a PPARa agonist on these parameters. Rats were either made diabetic with streptozotocin (55 mg/kg i.p.) and maintained for 10-14 days, or treated with the PPARa agonist fenofibrate (300mg/kg/day) for 4 wks. MTE-I and UCP3 protein expression, MTE-1 activity, palmitate export, and oxidative phosphorylation were measured in isolated cardiac mitochondria. Diabetes and fenofibrate increased cardiac MTE-I mRNA, protein and activity (approximately 4-fold compared to controls). This increase in activity was matched by a 6-fold increase in palmitate export in fenofibrate treated animals, despite no effect of either group on UCP3 protein expression. Both diabetes and fenofibrate caused a significant decrease in state III respiration of isolated mitochondria with pyruvate+malate as the substrate, but only diabetes reduced state III rates with palmitoylcarnitine. Conclusion: Both diabetes and specific PPARa activation increased MTE-I protein, activity, and palmitate export in the heart, with little effect on UCP3 protein expression.
Revised on March 26, 2007
Accepted on April 16, 2007
Diabetes and activation of peroxisome proliferator activated receptor alpha increase mitochondrial thioesterase I protein expression and activity in the heart
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