Plasma free fatty acids and peroxisome proliferator-activated receptor alpha 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 PPARalpha-/- and diabetic mice. Cardiac UCP2 and UCP3 were significantly lower in the PPARalpha-/- mouse than in the wild type. Treatment with the PPARalpha-specific agonist, WY-14,643, increased cardiac UCP2 and UCP3 levels in wild-type mice but did not alter UCP levels in PPARalpha-/- mice. Inhibition of beta-oxidation with etomoxir increased cardiac UCP2 and UCP3 levels in wild-type mice and UCP2 levels in PPARalpha-/- mice but did not alter UCP3 levels in PPARalpha-/- mice. Streptozotocin treatment, which increased circulating FFAs by 91%, did not alter cardiac UCP2 levels in wild-type or PPARalpha-/- mice but increased UCP3 levels in wild-type, and not in PPARalpha-/-, 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 PPARalpha to increase cardiac UCP3 levels, but cardiac UCP2 levels changed via PPARalpha-dependent and -independent mechanisms.
Murray
Andrew J
AJ
University Laboratory of Physiology, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.
Panagia
Marcello
M
Hauton
David
D
Gibbons
Geoffrey F
GF
Clarke
Kieran
K
D000818:Animals; D001835:Body Weight; D002352:Carrier Proteins / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D006706:Homeostasis; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D007473:Ion Channels; D008565:Membrane Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism*; D047493:PPAR alpha / Q000097:blood* / Q000172:deficiency*; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
D002352:Carrier Proteins; D004852:Epoxy Compounds; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D007473:Ion Channels; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D014280:Triglycerides; C000604390:Ucp2 protein, mouse; C000604393:Ucp3 protein, mouse; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; C006253:pirinixic acid; C054207:etomoxir