Regulation of fatty acid oxidation of the heart by MCD and ACC during contractile stimulation

Abstract

We tested the hypothesis that the level of malonyl-CoA, as well as the corresponding rate of total fatty acid oxidation of the heart, is regulated by the opposing actions of acetyl-CoA carboxylase (ACC) and malonyl-CoA decarboxylase (MCD). We used isolated working rat hearts perfused under physiological conditions. MCD in heart homogenates was measured specifically by14CO2production from [3-14C]malonyl-CoA, and ACC was measured specifically based on the portion of total carboxylase that is citrate sensitive. Increased heart work (1 μM epinephrine + 40% increase in afterload) elicited a 40% increase in total β-oxidation of exogenous plus endogenous lipids, accompanied by a 33% decrease in malonyl-CoA. The basal activity and citrate sensitivity of ACC (reflecting its phosphorylation state) and citrate content were unchanged. AMP levels were also unchanged. MCD activity, when measured at a subsaturating concentration of malonyl-CoA (50 μM), was increased by 55%. We conclude that physiological increments in AMP during the work transition are insufficient to promote ACC phosphorylation by AMP-stimulated protein kinase. Rather, increased fatty acid oxidation results from increased malonyl-CoA degradation by MCD.

Malonyl-CoA decarboxylase inhibition is selectively cytotoxic to human breast cancer cells

“…MCD activity assay, coenzyme-A and coenzyme-A derivative measurements and immunoblots Malonyl-CoA decarboxylase activity was assayed in 5 Â 10 5 MCF7 cells by trapping 14 CO 2 from the decarboxylation of [1,[3][4][5][6][7][8][9][10][11][12][13][14] C]malonyl-CoA as described (Goodwin and Taegtmeyer, 1999). The MCD inhibitor, bromopyruvic acid (Sigma), 1 mM, was used as a positive control.…”

“…Malonyl-CoA decarboxylase (MCD) (E.C. 4.1.1.9) acts to regulate malonyl-CoA levels through its decarboxylation back to acetyl-CoA (Figure 1) (Goodwin and Taegtmeyer, 1999). Inhibition of MCD affords another strategy to rapidly increase malonyl-CoA levels through decreasing its catabolism.…”

Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets

“…Previously, the notion was that the disposition of malonyl-CoA in the cytosol is toward biosynthesis of longchain fatty acids catalyzed by the fatty acid synthase. However, its levels at the mitochondrial membrane may be regulated by not only its synthesis by ACC2 but also by its degradation by the malonyl-CoA decarboxylase (MCD), an enzyme that is present in the mitochondria (29). Hence, it is our supposition that the ACC2, CPT1, and MCD, which are associated with the mitochondria, coordinate the acute regulation of fatty acid oxidation and may through malonyl-CoA function within the same mitochondrial vicinity.…”

Regulation of Malonyl-CoA Concentration and Turnover in the Normal Heart

“…The rate of turnover of malonyl-CoA is likely to be regulated by the cytosolic acetyl-CoA concentration and by the activities of ACC and MCD. The concentrations of cytosolic acetyl-CoA and malonyl-CoA in the heart are much lower than the K m of the two enzymes for their respective substrates (6,8). Thus, it is unlikely that the modulation of ACC and MCD activities exerts a tight control on malonyl-CoA turnover.…”

“…It is also an inhibitor of carnitine palmitoyltransferase I, a regulator of fatty acid oxidation in most tissues (1)(2)(3). A number of studies have documented the modulation by malonyl-CoA of fatty acid oxidation in the heart under physiological and pathological conditions, such as maturation (4), diabetes (5), increased cardiac work (6), and postischemic reperfusion (7). In the heart, malonyl-CoA formed by cytosolic acetyl-CoA carboxylase (ACC) 1 is, as far as is known, disposed only via decarboxylation catalyzed by malonyl-CoA decarboxylase (MCD).…”