Plasma Free Fatty Acids and Peroxisome Proliferator–Activated Receptor α in the Control of Myocardial Uncoupling Protein Levels

Plasma Free Fatty Acids and Peroxisome Proliferator–Activated Receptor α in the Control of Myocardial Uncoupling Protein Levels Andrew J. Murray 1 , Marcello Panagia 1 , David Hauton 2 , Geoffrey F. Gibbons 2 and Kieran Clarke 1 1 University Laboratory of Physiology, University of Oxford, Oxford, U.K. 2 Metabolic Research Laboratory, Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford, U.K. Address correspondence and reprint requests to Professor Kieran Clarke, University Laboratory of Physiology, University of Oxford, Parks Road, Oxford, OX1 3PT, U.K. E-mail: kieran.clarke{at}physiol.ox.ac.uk Abstract Diabetic patients have abnormal cardiac energy metabolism associated with high plasma free fatty acid (FFA) concentrations. We investigated whether high plasma FFAs increase mitochondrial uncoupling protein (UCP) levels in the mouse heart by activating the nuclear transcription factor peroxisome proliferator–activated receptor (PPAR)α. We used Western blotting to measure UCP protein levels in isolated cardiac mitochondria from PPARα −/− and diabetic mice. Cardiac UCP2 and UCP3 were significantly lower in the PPARα −/− mouse than in the wild type. Treatment with the PPARα-specific agonist, WY-14,643, increased cardiac UCP2 and UCP3 levels in wild-type mice but did not alter UCP levels in PPARα −/− mice. Inhibition of β-oxidation with etomoxir increased cardiac UCP2 and UCP3 levels in wild-type mice and UCP2 levels in PPARα −/− mice but did not alter UCP3 levels in PPARα −/− mice. Streptozotocin treatment, which increased circulating FFAs by 91%, did not alter cardiac UCP2 levels in wild-type or PPARα −/− mice but increased UCP3 levels in wild-type, and not in PPARα −/− , mice. The diabetic db/db mouse had 50% higher plasma FFA concentrations and elevated cardiac UCP2 and UCP3 protein levels. We conclude that high plasma FFAs activated PPARα to increase cardiac UCP3 levels, but cardiac UCP2 levels changed via PPARα-dependent and -independent mechanisms. FFA, free fatty acid PCr, phosphocreatine PPAR, peroxisome proliferator–activated receptor STZ, streptozotocin UCP, uncoupling protein Footnotes Accepted September 9, 2005. Received April 25, 2005. DIABETES