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

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.

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). We used Western blotting to measure UCP protein levels in isolated cardiac mitochondria from PPAR^–/– and diabetic mice. Cardiac UCP2 and UCP3 were significantly lower in the PPAR^–/– mouse than in the wild type. Treatment with the PPAR-specific agonist, WY-14,643, increased cardiac UCP2 and UCP3 levels in wild-type mice but did not alter UCP levels in PPAR^–/– mice. Inhibition of ß-oxidation with etomoxir increased cardiac UCP2 and UCP3 levels in wild-type mice and UCP2 levels in PPAR^–/– mice but did not alter UCP3 levels in PPAR^–/– mice. Streptozotocin treatment, which increased circulating FFAs by 91%, did not alter cardiac UCP2 levels in wild-type or PPAR^–/– mice but increased UCP3 levels in wild-type, and not in PPAR^–/–, 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 PPAR to increase cardiac UCP3 levels, but cardiac UCP2 levels changed via PPAR-dependent and -independent mechanisms.

Abbreviations: FFA, free fatty acid; PCr, phosphocreatine; PPAR, peroxisome proliferator–activated receptor; STZ, streptozotocin; UCP, uncoupling protein

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