Plasma free fatty acids and peroxisome proliferator-activated receptor α in the control of myocardial uncoupling protein levels

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