Abstract
We investigated the impact of acetate and propionate on the oxidation of oleate in rat hearts perfused with 0.4 mM [1-13C]oleate + various concentrations of [1,2-13C2]acetate or propionate. We assayed the contributions of oleate and acetate to the acetyl moiety of citrate (a probe of mitochondrial acetyl-CoA) and to malonyl-CoA. We found that acetate, even at low concentration, markedly inhibits the oxidation of [1-13C]oleate, without changes in [malonyl-CoA]. Also, 2 mM propionate (which does not generate acetyl-CoA in heart) decreased the contribution of 0.4 mM [1-13C]oleate to mitochondrial acetyl-CoA (from 67 to 35%), with a surprising 50% decrease in [malonyl-CoA]. In the presence of [1-13C]oleate and [1,2-13C2]acetate, the M2 labeling of malonyl-CoA was lower than that of the acetyl of citrate. This is not compatible with a cytosolic site of acetate activation in the heart. In contrast, the M1 labeling of malonyl-CoA was higher than that of the acetyl of citrate. This reflects the contribution of peroxisomal oxidation of [1-13C]oleate to the supply of acetyl-CoA used for malonyl-CoA synthesis. The profound inhibition of fatty acid oxidation by acetate may contribute to the accumulation of long-chain fatty acyl-CoAs and carnitines in the heart, and to the cardiomyopathies observed in alcoholics and hemodialyzed patients. (Supported by NIH Roadmap grant R33DK070291, and grant 2PO1AG015885)
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