Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor alpha in the adult rodent heart

Relatively little is known concerning the regulation of uncoupling proteins (UCPs) in the heart. We investigated in the adult rodent heart 1) whether changes in workload, substrate supply, or cytokine (TNF-alpha) administrati on affect UCP-2 and UCP-3 expression, and 2) whether peroxisome proliferato r-activated receptor alpha (PPAR alpha) regulates the expression of either UCP-2 or UCP-3. Direct comparisons were made between cardiac and skeletal m uscle. UCP-2, UCP-3, and PPAR alpha expression were reduced when cardiac wo rkload was either increased (pressure overload by aortic constriction) or d ecreased (mechanical unloading by heterotopic transplantation). Similar res ults were observed during cytokine administration. Reduced dietary fatty ac id availability resulted in decreased expression of both cardiac UCP-2 and UCP-3. However, when fatty acid (the natural ligand for PPAR alpha) supply was increased thigh-fat feeding, fasting, and STZ-induced diabetes), cardia c UCP-3 but not UCP-2 expression increased. Comparable results were observe d in rats treated with the specific PPAR alpha agonist WY-14,643, The level of cardiac UCP-3 but not UCP-2 expression was severely reduced (20-fold) i n PPAR alpha (-/-) mice compared to wild-type mice. These results suggest t hat in the adult rodent heart, UCP-3 expression is regulated by PPAR alpha, In contrast, cardiac UCP-2 expression is regulated in part by a fatty acid -dependent, PPAR alpha -independent mechanism.