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Acetyl-CoA carboxylase regulation of fatty acid oxidation in the heart.

1993; Elsevier BV; Volume: 268; Issue: 34 Linguagem: Inglês

10.1016/s0021-9258(19)74465-2

1083-351X

Maruf Saddik, James L. Gamble, Lee A. Witters, Gary D. Lopaschuk,

Adipose Tissue and Metabolism

The role of acetyl-coenzyme A carboxylase (ACC) in regulating fatty acid oxidation was investigated in isolated fatty acid perfused working rat hearts.Overall fatty acid oxidation rates were determined by addition of 1.2 m M ['Hlpalmitate to the perfusate of hearts in which the endogenous triglyceride pool was prelabeled with [14C]palmitate.Rates of both exogenous and endogenous fatty acid oxidation were measured by simultaneous measurement of 'HzO and 14COz production, respectively.A second series of hearts were perfused under similar conditions except that [U-"C]glucose was present in the perfusate for measurement of glucose oxidation rates.Addition of dichloroacetate (DCA, 1 mM) to the perfusate resulted in a dramatic stimulation of glucose oxidation (a 41 1% increase), with a parallel decrease in fatty acid oxidation (from 305 f 51 to 206 f 40 nmol/g dry weight *min-unit work).DCA treatment increased the contribution of glucose oxidation to ATP production from 7.1 to 30.6%, while decreasing the contribution of overall fatty acid oxidation from 92.9 to 69.4%.Tissue levels of malonyl-CoA in hearts treated with DCA were higher compared to controls (14.0 f 0.6 and 10.0 f 0.7 nmol/g dry weight, respectively) and were negatively correlated ( r = -0.85)with overall fatty acid oxidation rates.Acetyl-coA levels were also significantly higher in DCA-treated hearts, and a positive correlation ( r = 0.88) was seen between myocardial acetyl-coA and malonyl-CoA levels.This suggests that DCA treatment increased the supply of acetyl-coA for ACC.Western blots revealed the presence of both the 280-kDa (ACC-280) and the 265-kDa (ACC-265) isoforms of ACC in cardiac tissue, with a predominance of ACC-280.The activity of ACC extracted from hearts was similar in both groups when assayed under optimal conditions of acetyl-coA and citrate.However, using affinity purified ACC, it was demonstrated that heart ACC (predominantly ACC-280) had a higher K, for