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Journal of Lipid Research, Vol. 48, 1511-1517, July 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Diabetes or peroxisome proliferator-activated receptor agonist increases mitochondrial thioesterase I activity in heart

Kristen L. King^*, Martin E. Young, Janos Kerner, Hazel Huang^*, Karen M. O'Shea, Stefan E. H. Alexson^**, Charles L. Hoppel and William C. Stanley^1,*,,

^* Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030
Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH 44106
^** Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital at Huddinge, Stockholm, Sweden
Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106
Department of Medicine, Division of Cardiology, University of Maryland School of Medicine, Baltimore, MD 21201

Published, JLR Papers in Press, April 16, 2007.

¹ To whom correspondence should be addressed. e-mail: wstanley{at}medicine.umaryland.edu

Peroxisome proliferator-activated receptor (PPAR) 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 about MTE-I activity; thus, we investigated the effects of diabetes and treatment with a PPAR agonist on these parameters. Rats were either made diabetic with streptozotocin (55 mg/kg ip) and maintained for 10–14 days or treated with the PPAR agonist fenofibrate (300 mg/kg/day) for 4 weeks. 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 (4-fold compared with controls). This increase in activity was matched by a 6-fold increase in palmitate export in fenofibrate-treated animals, despite there being no effect in either group on UCP3 protein expression. Both diabetes and fenofibrate caused significant decreases in state III respiration of isolated mitochondria with pyruvate + malate as the substrate, but only diabetes reduced state III rates with palmitoylcarnitine. Both diabetes and specific PPAR activation increased MTE-I protein, activity, and palmitate export in the heart, with little effect on UCP3 protein expression.

Supplementary key words cardiac • fatty acids • lipotoxicity

Abbreviations: IFM, interfibrillar mitochondria; MTE-I, mitochondrial thioesterase I; P/O, ADP-to-oxygen ratio; PPAR, peroxisome proliferator-activated receptor ; RCR, respiratory control ratio; SSM, subsarcolemmal mitochondria; UCP3, uncoupling protein 3

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