Submitted to: Journal of Lipid Research
Publication Type: Peer reviewed journal
Publication Acceptance Date: 4/16/2007
Publication Date: 4/16/2007
Citation: King, K.L., Young, M.E., Kerner, J., Hanug, H., O'Shea, K.M., Alexson, S.E.H., Hoppel, C.L., Stanley, W.C. 2007. Diabetes or peroxisome proliferator-activated receptor alpha agonist increases mitochondrial thioesterase I activity in heart. Journal of Lipid Research. 48:1511-1517. Interpretive Summary: During conditions in which fat levels are elevated in the blood (e.g., diabetes), the heart increases its use of fats. However, fats are not a very efficient energy source, in that more oxygen is required to generate the same energy from fat, compared to glucose. This becomes important if a person has problems with the delivery of oxygen to the heart cells, which is a common feature of heart disease. The present study sought to improve our understanding of why fats are a less efficient fuel source. The results show that fats increased the activity of an enzyme call mitochondrial thioesterase I, which may contribute to fats being a less efficient fuel source.
Technical Abstract: 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.