Diabetes or peroxisome proliferator-activated receptor alpha agonist increases mitochondrial thioesterase I activity in heart.
Peroxisome proliferator-activated receptor alpha (PPAR alpha) 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 alpha 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 alpha 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 ( approximately 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 alpha activation increased MTE-I protein, activity, and palmitate export in the heart, with little effect on UCP3 protein expression.
King
Kristen L
KL
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA.
Young
Martin E
ME
Kerner
Janos
J
Huang
Hazel
H
O'Shea
Karen M
KM
Alexson
Stefan E H
SE
Hoppel
Charles L
CL
Stanley
William C
WC
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D011345:Fenofibrate / Q000494:pharmacology*; D007473:Ion Channels / Q000096:biosynthesis; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D010101:Oxygen Consumption / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists*; D019308:Palmitic Acid / Q000378:metabolism; D010170:Palmitoyl-CoA Hydrolase / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000071247:Uncoupling Protein 3
D007473:Ion Channels; D024101:Mitochondrial Proteins; D047493:PPAR alpha; D012333:RNA, Messenger; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; D019308:Palmitic Acid; D010170:Palmitoyl-CoA Hydrolase; D011345:Fenofibrate