Malonyl-CoA, fuel sensing, and insulin resistance

Abstract

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 β-isoform of acetyl-CoA carboxylase (ACCβ). This can occur by at least two mechanisms: one involving cytosolic citrate, an allosteric activator of ACCβ and a precursor of its substrate cytosolic acetyl-CoA, and the other involving changes in ACCβphosphorylation. 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 ACCβ 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 β-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.

Adipose tissue distribution and risk of metabolic disease: does thiazolidinedione-induced adipose tissue redistribution provide a clue to the answer?

“…Visceral obesity has since been reproducibly implicated as an independent risk factor for insulin resistance and glucose intolerance, which predict type 2 diabetes and cardiovascular disease in different ethnic populations [1,2]. One of the hypotheses proposed to explain the link between visceral obesity and the chronic complex metabolic diseases is the visceral/portal hypothesis, in which: (1) an increased hepatic uptake of the 'first pass' of NEFAs released from visceral fat lipolysis into the portal vein may reduce the hepatic extraction of insulin and thus impair insulin-induced suppression of hepatic gluconeogenesis, leading to increased endogenous glucose production; (2) an increased hepatic lipase activity may remove lipids from LDL and HDL, which, in combination with the decreased degradation of apolipoprotein B and the increased esterification of NEFAs, results in the increased synthesis and secretion of VLDL and smaller, denser LDL and HDL particles into the systemic circulation, distorting the circulating lipid profile; and (3) an increased systemic NEFA flux may impair insulin action in skeletal muscle and other key tissues via malonyl-CoA/acetyl-CoA carboxylase β fuel-sensing and regulation mechanisms [1,2,6].…”

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

“…Inhibition of ACC, with consequent lowering of tissue malonyl-CoA, occurs as a result of the increased deficit between the rate of ATP production and ATP utilization that leads to increased formation of AMP and activation of AMPK. The ensuing fall in tissue malonylCoA content activates fatty acid oxidation [4,62,63]. Moreover, in untrained rats and humans, graded exercise results in a fall in …”

“…In insulin-resistant states the TAG content of muscle is increased [112], presumably due to the combination of the chronic elevation of the rate of delivery of plasma NEFA and glucose to the tissue (see Scheme 5). It has been pointed out that muscle malonyl-CoA content is also elevated in several models of insulin resistance [4,113]. This is expected to predispose muscle cells to accumulate intracellular TAG when plasma NEFA are elevated, especially when blood glucose is also elevated.…”

“…However, it is possible that other malonyl-CoAutilizing enzymes may be involved in terminating the malonylCoA signal to the cell in non-lipogenic tissues. Such a role has been suggested for the fatty acid chain-elongation system [17] and for malonyl-CoA decarboxylase [4,18]. However, malonylCoA decarboxylase is not thought to have a cytosolic distribution in mammalian tissues [19].…”

Dietary and lifestyle interventions in the management of the metabolic syndrome: present status and future perspective

“…It has indeed been proposed that intracellular fatty acyl CoA may directly inhibit muscle glucose transport by impairing insulin signaling . According to this scheme, impaired muscle lipid oxidation, possibly related to a low muscle oxidative capacity (as often observed in insulin resistant individuals; Kelley & Simoneau, 1997) would lead to accumulation of muscle fatty acyl CoA and insulin resistance (Ruderman et al, 1999). Recent interest has focused on the potential role of intramyocellular lipids (ie lipids stored within the skeletal muscle fibers) in the pathogenesis of insulin resistance.…”