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

Abstract

Peroxisome proliferator-activated 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 about 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 ip) and maintained for 10-14 days or treated with the PPARa 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 1 malate as the substrate, but only diabetes reduced state III rates with palmitoylcarnitine. Both diabetes and specific PPARa activation increased MTE-I protein, activity, and palmitate export in the heart, with little effect on UCP3 protein expres-

Upregulation of Fatty Acyl-CoA Thioesterases in the Heart and Skeletal Muscle of Rats Fed a High-Fat Diet

“…Moreover, the mechanisms underlying the induction of ACOT7 in the heart and skeletal muscle are also unclear, while the induction of ACOT1 and ACOT2 seems to be mediated by PPAR alpha. 7,25,26) We have pointed out beneficial aspects of ACOT upregulation with respect to alleviation of lipotoxicity and insulin resistance. However, it has not been determined whether the lipotoxic conditions detrimental to obese animals are associated with maladaptation of ACOT expression, because our dietinduced obesity model fed a high-fat diet, but not a Western diet, 21) showed no apparent metabolic problems.…”

“…20,21) Although the roles of ACOT in lipid metabolism have not been fully established, a model concerning the roles of ACOT1 and ACOT2 is emerging. 7,8,[20][21][22][23] In this model, fatty acids entering a cell across the plasma membrane are rapidly activated to acyl-CoA and partitioned into the oxidative and nonoxidative metabolic pathways. 20,21) In the heart and soleus muscle, where the expression level of cytosolic ACOT1 is very low, mitochondrial fatty acid oxidation may be the default primary pathway for acyl-CoA metabolism.…”

“…Thus, an additional futile cycle mediated by ACOT2 would be promoted. 7,8,[21][22][23] In the futile cycle, AMP produced by acyl-CoA synthetase provides an adenine nucleotide substrate for proton gradientdriven ATP synthesis, which may serve to maintain the expected ETC activity.…”

“…4) However, acyl-CoA thioesterase (ACOT) exists within the mitochondrial matrix of mammalian cells 5) and its expression is expected to be upregulated in response to fatty acid overload, as demonstrated in diabetic and fasted animals. 6,7) ACOT comprises a group of enzymes that are localized in multiple compartments in cells and catalyze the hydrolysis of long-chain acyl-CoA thioesters to free fatty acids and CoA-SH. For example, ACOT1 (formerly known as CTE-I or ACH2) and ACOT7a (CTE-II, BACH or ACT) are localized in the cytosol while ACOT2 (MTE-I or ARTISt) and ACOT7b (MTE-II or LACH1) are present in mitochondria.…”

Fatty acid oxidation in cardiac and skeletal muscle mitochondria is unaffected by deletion of CD36

“…Recent studies on cardiac mitochondria noted the hydrolysis of LCFA-CoA to LCFA by mitochondrial thioesterase I (MTE-I) in the matrix, and these LCFAs are subsequently exported out of the mitochondria by an unidentified protein carrier [7;8]. It has been proposed that uncoupling protein 3 (UCP3) is responsible for LCFA export from the matrix [7], however we recently observed that both MTE-I and fatty acid export are up-regulated ∼5-fold by diabetes without a significant change in UCP3 protein levels [8]. A likely candidate for this process is CD36, however it's role in mitochondrial LCFA export has not been assessed.…”