Malonyl-CoA is an intermediate in the de novo synthesis of fatty acids. Stimulation of the de novo lipogenesis pathway therefore increases the production of malonyl-CoA. Malonyl-CoA is an important intermediate in this pathway because it allosterically inhibits a number of key enzymes (this means it binds to the enzyme at the non-active site and alters the conformation of the proteins, modifying their catalytic activity). In particular malonyl-CoA inhibits the carnitine palmitoyltransferase (CPT) 1 enzyme, an enzyme required for the transport of fatty acids to the mitochondria for oxidation. Therefore the synthesis of fatty acids inhibits the oxidation of fatty acids, which prevents inefficiency in the cell. As the synthesis of fatty acids (and subsequently triglycerides) are under the control of insulin, it can be surmised that insulin prevents the oxidation of fatty acid oxidation through the accumulation of malonyl-coA in the cell. As insulin levels drop, malonyl-CoA levels drop concomitantly and fatty acid oxidation proceeds.
Acetyl-CoA carboxylase is the enzyme required for the synthesis of malonyl-CoA. Acetyl-CoA carboxylase is in turn regulated by the levels of citrate in the cell. As cellular energy levels rise due to insulin stimulated glucose uptake, anabolic pathways predominate. This results in citrate, an intermediate in the main energy producing pathway of the cell (the citric acid cycle) accumulating. This accumulating citrate can allosterically stimulate acetyl-CoA carboxylase, which in turn increases the synthesis of fatty acids through an increase in the concentration of the malonyl-CoA substrate. As the fatty acids from the de novo lipogenesis pathway are formed, they are esterified to glycerol, and this results in triglycerides. These are then packaged into the very low density lipoprotein (VLDL) particle, and enter circulation. Removal of fatty acids from the VLDL particle in peripheral tissues (usually adipocytes) result in a change in the density of the particle which becomes low density lipoprotein (LDL).
The production of fatty acids in this way is a normal part of the postprandial period where insulin dominates the hormonal milieu. As insulin and glucose levels fall, the energy provided to the cell falls, citrate levels fall, the stimulation of acetyl-CoA carboxylase is removed and the levels of malonyl-CoA, fatty acid and triglycerides fall. The postprandial period is characterised by glucagon and this stimulates catabolic pathways that result in the oxidation of fatty acids. However, in the insulin resistant state, fasting insulin and fasting glucose levels remain elevated. This prevents the oxidation of fatty acids through citrate stimulated of the de novo lipogenesis pathway. The result is that the metabolic pathways that normally ebb and flow between insulin and glucagon, become locked into an anabolic pattern dominated by insuling. The metabolic changes that result from this include an increase in the risk of Western lifestyle diseases as well as metabolic changes such as raised levels of VLDL and LDL.
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