Regulation of myocardial fatty acid oxidation by substrate supply.
We tested the hypothesis that myocardial substrate supply regulates fatty acid oxidation independent of changes in acetyl-CoA carboxylase (ACC) and 5'-AMP-activated protein kinase (AMPK) activities. Fatty acid oxidation was measured in isolated working rat hearts exposed to different concentrations of exogenous long-chain (0.4 or 1.2 mM palmitate) or medium-chain (0.6 or 2.4 mM octanoate) fatty acids. Fatty acid oxidation was increased with increasing exogenous substrate concentration in both palmitate and octanoate groups. Malonyl-CoA content only rose as acetyl-CoA supply from octanoate oxidation increased. The increases in octanoate oxidation and malonyl-CoA content were independent of changes in ACC and AMPK activity, except that ACC activity increased with very high acetyl-CoA supply levels. Our data suggest that myocardial substrate supply is the primary mechanism responsible for alterations in fatty acid oxidation rates under nonstressful conditions and when substrates are present at physiological concentrations. More extreme variations in substrate supply lead to changes in fatty acid oxidation by the additional involvement of intracellular regulatory pathways.
Longnus
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McDonald Research Laboratories/iCAPTURE Centre, Department of Pathology and Laboratory Medicine, University of British Columbia and St. Paul's Hospital/Providence Health Care, Vancouver, British Columbia V6Z 1Y6, Canada.
Wambolt
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RB
Barr
R L
RL
Lopaschuk
G D
GD
Allard
M F
MF
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D006019:Glycolysis; D066298:In Vitro Techniques; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000494:pharmacology; D013379:Substrate Specificity
D005227:Fatty Acids; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D008316:Malonyl Coenzyme A; D000105:Acetyl Coenzyme A; D000263:Adenylate Kinase; D000103:Acetyl-CoA Carboxylase; C031143:AICA ribonucleotide