Evidence for mitochondrial thioesterase 1 as a peroxisome proliferator-activated receptor-[alpha]-regulated gene in cardiac and skeletal muscle

Evidence for mitochondrial thioesterase 1 as a peroxisome proliferator-activated receptor-[alpha]-regulated gene in cardiac and skeletal muscle. Am J Physiol Endocrinol Metab 287: E888-E895, 2004. First published August 3, 2004; doi:10.1152/ajpendo.00190.2004.--The physiological role of mitochondrial thioesterase 1 (MTE1) is unknown. It was proposed that MTE1 promotes fatty acid (FA) oxidation (FAO) by acting in concert with uncoupling protein (UCP)3. We previously showed that ucp3 is a peroxisome proliferator-activated receptor-[alpha] (PPAR[alpha])-regulated gene, allowing induction when FA availability increases. On the assumption that UCP3 and MTE1 act in partnership to increase FAO, we hypothesized that mte1 is also a PPAR[alpha]-regulated gene in cardiac and skeletal muscle. Using real-time RT-PCR, we characterized mte1 gene expression in rat heart and soleus muscles. Messenger RNA encoding for mte1 was 3.2-fold higher in heart than in soleus muscle. Cardiac mte1 mRNA exhibited modest diurnal variation, with 1.4-fold higher levels during dark phase. In contrast, skeletal muscle mte1 mRNA remained relatively constant over the course of the day. High-fat feeding, fasting, and streptozotocin-induced diabetes, interventions that increase FA availability, muscle PPAR[alpha] activity, and muscle FAO rates, increased mte1 mRNA in heart and soleus muscle. Conversely, pressure overload and hypoxia, interventions that decrease cardiac PPAR[alpha] activity and FAO rates, repressed cardiac mte1 expression. Specific activation of PPAR[alpha] in vivo through WY-14643 administration rapidly induced mte1 mRNA in cardiac and skeletal muscle. WY-14643 also induced mte1 mRNA in isolated adult rat cardiomyocytes dose dependently. Expression of mte1 was markedly lower in hearts and soleus muscles isolated from PPAR[alpha]-null mice. Alterations in cardiac and skeletal muscle ucp3 expression mirrored that of mte1 in all models investigated. In conclusion, mte1, like ucp3, is a PPAR[alpha]-regulated gene in cardiac and skeletal muscle. nonesterified fatty acids; uncoupling protein 3; diurnal variations; diabetes; fasting