Cytosol lipogenesis

Fatty acids are synthesized by an extramitochondrial system, which is responsible for the complete synthesis of palmitate from acetyl-CoA in the cytosol. In the rat, the pathway is well represented in adipose tissue and liver, whereas in humans adipose tissue may not be an important site, and liver has only low activity. In birds, lipogenesis is confined to the liver, where it is particularly important in providing lipids for egg formation. In most mammals, glucose is the primary substrate for lipogenesis, but in ruminants it is acetate, the main fuel molecule produced by the diet. Critical diseases of the pathway have not been reported in humans. However, inhibition of lipogenesis occurs in type 1 (insulin-de-pendent) diabetes mellitus, and variations in its activity may affect the nature and extent of obesity. 

THE MAIN PATHWAY FOR DE NOVO SYNTHESIS OF FATTY ACIDS (LIPOGENESIS) OCCURS IN THE CYTOSOL... 

Pyruvate carboxylase is also important in lipogenesis. Citrate is transported out of mitochondria and cleaved in the cytosol to provide acetyl CoA for fatty acid synthesis the resultant oxaloacetate is reduced to malate, which undergoes oxidative decarboxylation to pyruvate, a reaction that provides at least half of the NADPH required for fatty acid synthesis. Pyruvate reenters the mitochondria and is carboxylated to oxaloacetate to maintain the process. 

Lipogenesis is controlled by a number of mechanisms, including allosteric effectors, covalent modification, and availability of substrate. Pyruvate is an excellent potential precursor for fatty acids, particularly in the liver. One of the difficulties encountered is that pyruvate can proceed to acetyl CoA in the mitochondrion, however, acetyl CoA in the mitochondrion will not directly produce fatty-acid synthesis because this process occurs in the cytosol. 

Acetyl CoA is converted to malonyl CoA and into fatty acids as described previously. The enzyme that carries out the first committed step for fatty-acid synthesis, acetyl CoA carboxylase, is finely controlled both allosterically and covalently. This enzyme can occur in a monomeric inactive form or a polymeric active form. One factor that affects this is citrate, which stimulates the polymeric or active form of acetyl CoA carboxylase. Thus, citrate plays an important role in lipogenesis as (1) a source of cytosolic acetyl CoA, (2) an allosteric positive effector of acetyl CoA carboxylase, and (3) a provider of oxaloacetate in the cytosol, which can allow transhydrogenation from NADH to NADPH. An allosteric inhibitor of acetyl CoA carboxylase that causes dissociation to the monomeric form is fatty-acyl CoA. Thus, if exogenous fatty acids are available, there is little reason to synthesize more fatty acids. Fatty-acyl CoA in the cytosol decreases malonyl CoA formation by inhibiting acetyl CoA carboxylase. 

A short-chain specific acetyl-CoA synthetase that is present in mammalian mitochondria has been purified and its cDNA has been cloned. This 71-kDa enzyme, which is most active with acetate as a substrate but exhibits some activity towards propionate, has been detected in mitochondria of heart, skeletal muscle, kidney, adipose tissue, and intestine, but not in mitochondria of liver. A cytosolic 78-kDa acetyl-CoA synthetase has been identified in liver, intestine, adipose tissue, and mammary gland, all of which have high lipogenic activities. Expression studies support the hypothesis that the cytosolic enzyme synthesizes acetyl-CoA for lipogenesis, whereas the mitochondrial acetyl-CoA synthetase activates acetate destined for oxidation (T.T. Yamamoto, 2(X)1). 

Windsor Zammit, 1990). In nuimmalian tissues, an increase in the concentration of malonyl-CoA in the cytosol prevents acyl-CoAs from entering the mitochondria. This ensures that when fatty acid biosynthesis is active, /3-oxidation is inhibited. However in the liver of domestic fowl, the concentration of malonyl-CoA does not increase sufficiently to inhibit the transferase, and so it appears that both lipogenesis and fatty acid oxidation can occur simultaneously in liver at a significant rate (Griffin et al, 1990). 

A glance at current knowledge of regulation of lipogenesis will be useful to point out problems that need to be examined in vascular tissue. Regulation of the cytosol fatty acid synthetic machinery has been excellently reviewed in Advances in Lipid Research in 1967 by Majerus and Vagelos, and other fine reviews too numerous to cite are available. The following discussion is not intended, therefore, as an exhaustive review. 

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