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1 Diabetes Unit, Section of Endocrinology and Departments of Medicine and Physiology, Boston University Medical Center, Boston, Massachusetts 02118; and 2 Endocrine-Metabolism Division, Department of Medicine and Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755
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
-isoform of acetyl-CoA carboxylase
(ACC
). This can occur by at
least two mechanisms: one involving cytosolic citrate, an allosteric
activator of ACC and a
precursor of its substrate cytosolic acetyl-CoA, and the other
involving changes in ACC 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
ACC 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 -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.
acetyl-CoA carboxylase; AMP-activated protein kinase; cytosolic citrate; glucose-fatty acid cycle; exercise; obesity; protein kinase C
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