MALONYL-COA REGULATION IN SKELETAL-MUSCLE - ITS LINK TO CELL CITRATE AND THE GLUCOSE-FATTY ACID CYCLE

Malonyl-CoA is an inhibitor of carnitine palmitoyltransferase I, the e nzyme that controls the oxidation of fatty acids by regulating their t ransfer into the mitochondria. Despite this, knowledge of how malonyl- CoA levels are regulated in skeletal muscle, the major site of fatty a cid oxidation, is limited. Two- to fivefold increases in malonyl-CoA o ccur in rat soleus muscles incubated with glucose or glucose plus insu lin 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 ma lonyl-CoA levels in the incubated soleus. The increases in malonyl-CoA in all of these situations correlated closely with increases in the c oncentration of citrate (r(2) = 0.64) and to an even greater extent th e sum of citrate plus malate (r(2) = 0.90), an antiporter for citrate efflux from the mitochondria. Where measured, no increase in the activ ity of acetyl-CoA carboxylase (ACC) was found. Inhibition of ATP citra te lyase with hydroxy-citrate markedly diminished the increases in mal onyl-CoA in these muscles, indicating that citrate was the major subst rate for the malonyl-CoA precursor, cytosolic acetyl-CoA. Studies with enzyme purified by immunoprecipitation indicated that the observed in creases in citrate could have also allosterically activated ACC. The r esults suggest that in the presence of glucose, insulin and acetoaceta te acutely increase malonyl-CoA levels in the incubated soleus by incr easing the cytosolic concentration of citrate. This novel mechanism co uld complement the glucose-fatty acid cycle in determining how muscle chooses its fuels. It could also provide a means by which glucose acut ely modulates signal transduction in muscle and other cells (e.g., the pancreatic beta-cell) in which its metabolism is determined by substr ate availability.