Malonyl-CoA regulation in skeletal muscle: its link to cell citrate and the glucose-fatty acid cycle

Abstract

Malonyl-CoA is an inhibitor of carnitine palmitoyltransferase I, the enzyme that controls the oxidation of fatty acids by regulating their transfer into the mitochondria. Despite this, knowledge of how malonyl-CoA levels are regulated in skeletal muscle, the major site of fatty acid oxidation, is limited. Two- to fivefold increases in malonyl-CoA occur in rat soleus muscles incubated with glucose or glucose plus insulin for 20 min [Saha, A. K., T. G. Kurowski, and N. B. Ruderman. Am. J. Physiol. 269 (Endocrinol. Metab. 32): E283-E289, 1995]. In addition, as reported here, acetoacetate in the presence of glucose increases malonyl-CoA levels in the incubated soleus. The increases in malonyl-CoA in all of these situations correlated closely with increases in the concentration of citrate (r2 = 0.64) and to an even greater extent the sum of citrate plus malate (r2 = 0.90), an antiporter for citrate efflux from the mitochondria. Where measured, no increase in the activity of acetyl-CoA carboxylase (ACC) was found. Inhibition of ATP citrate lyase with hydroxycitrate markedly diminished the increases in malonyl-CoA in these muscles, indicating that citrate was the major substrate for the malonyl-CoA precursor, cytosolic acetyl-CoA. Studies with enzyme purified by immunoprecipitation indicated that the observed increases in citrate could have also allosterically activated ACC. The results suggest that in the presence of glucose, insulin and acetoacetate acutely increase malonyl-CoA levels in the incubated soleus by increasing the cytosolic concentration of citrate. This novel mechanism could complement the glucose-fatty acid cycle in determining how muscle chooses its fuels. It could also provide a means by which glucose acutely modulates signal transduction in muscle and other cells (e.g., the pancreatic beta-cell) in which its metabolism is determined by substrate availability.

Time-course effects of endurance training on fat oxidation in sedentary elderly people

“…37 This could be associated with the stimulant effect of insulin and glucose on the production of malonyl-CoA, a powerful inhibitor of the FFA carrier into the mitochondria. 38 Therefore, higher glucose availability and a lower intra-mitochondrial FFA availability could promote glucose oxidation at the expense of FFA oxidation. In other respects, our results may suggest a down-regulation of the sympathetic nervous system activity andaor of the sensitivity to catecholamines.…”

The malonyl-CoA–long-chain acyl-CoA axis in the maintenance of mammalian cell function

“…Although the activity of ATP citrate-lyase is very low in muscle [67], the absolute magnitude of the flux leading from mitochondrial acetyl-CoA to cytosolic malonylCoA is immaterial for the maintenance of muscle malonyl-CoA concentrations, as rate of malonyl-CoA utilization is also low (see above). Interestingly, a stronger correlation is found between malonyl-CoA content of muscle and the combined total tissue concentrations of citrate plus malate rather than citrate alone [68,69]. In muscle, both these metabolites arise mainly from mitochondrial oxaloacetate due to the low activity of ATPcitrate lyase [67].…”

Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

“…Malonyl CoA was determined radio-enzymatically by a slight modification of a previously published method [35,36]. The activity of AMPK (α1 and α2 subunits) [16] and phosphorylation of Thr 172 on the AMPK α subunit (a measure of AMPK activation) [31] were assayed as described previously.…”