Malonyl-CoA is an allosteric inhibitor of
carnitine palmitoyltransferase (
CPT) I, the
enzyme that controls the transfer of long-chain fatty acyl (LCFA)-CoAs into the mitochondria where they are oxidized. In rat skeletal muscle, the formation of
malonyl-CoA is regulated acutely (in minutes) by changes in the activity of the beta-
isoform of
acetyl-CoA carboxylase (ACCbeta). This can occur by at least two mechanisms: one involving cytosolic
citrate, an allosteric activator of ACCbeta and a precursor of its substrate cytosolic
acetyl-CoA, and the other involving changes in ACCbeta phosphorylation. Increases in cytosolic
citrate leading to an increase in the concentration of
malonyl-CoA occur when muscle is presented with
insulin and
glucose, or when it is made inactive by
denervation, in keeping with a diminished need for
fatty acid oxidation in these situations. Conversely, during exercise, when the need of the muscle cell for
fatty acid oxidation is increased, decreases in the
ATP/
AMP and/or
creatine phosphate-to-
creatine ratios activate an
isoform of an
AMP-activated protein kinase (AMPK), which phosphorylates ACCbeta and inhibits both its basal activity and activation by
citrate. The central role of cytosolic
citrate links this
malonyl-CoA regulatory mechanism to the
glucose-
fatty acid cycle concept of Randle et al. (P. J. Randle, P. B. Garland. C. N. Hales, and E. A. Newsholme. Lancet 1: 785-789, 1963) and to a mechanism by which
glucose might autoregulate its own use. A similar
citrate-mediated
malonyl-CoA regulatory mechanism appears to exist in other tissues, including the pancreatic beta-cell, the heart, and probably the central nervous system. It is our hypothesis that by altering the cytosolic concentrations of LCFA-
CoA and diacylglycerol, and secondarily the activity of one or more
protein kinase C isoforms, changes in
malonyl-CoA provide a link between fuel metabolism and signal transduction in these cells. It is also our hypothesis that dysregulation of the
malonyl-CoA regulatory mechanism, if it leads to sustained increases in the concentrations of
malonyl-CoA and cytosolic LCFA-
CoA, could play a key role in the pathogenesis of
insulin resistance in muscle. That it may contribute to abnormalities associated with the
insulin resistance syndrome in other tissues and the development of
obesity has also been suggested. Studies are clearly needed to test these hypotheses and to explore the notion that exercise and some pharmacological agents that increase
insulin sensitivity act via effects on
malonyl-CoA and/or cytosolic LCFA-
CoA.