Lipogenesis

The synthesis of palmitic acid occurs in the cytosol, from acetyl-CoA. When glucose is abundant and the amount of citrate in the mitochondrial matrix exceeds the demand by the citric acid cycle, the excess citrate is transported out of the mitochondria into the cytosol (Fig. 13-8). Citrate in the cytosol is the source of acetyl groups for fatty acid synthesis, and its metabolism there involves the following enzyme reactions  

For the conversion of pyruvate to oxaloacetate and the formation of citrate in the mitochondrion, see Chap. 12. Acetyl-CoA for fatty acid synthesis is converted to malonyl-CoA this reaction is catalyzed by acetyl-CoA carboxylase. Seven molecules of acetyl-CoA are converted to malonyl-CoA for the synthesis of one molecule of palmitic acid. 

In the formation of malonyl-CoA via acetyl-CoA carboxylase, biotin which is tightly bound to the enzyme as a prosthetic group acts as a carrier of a carboxyl group that is transferred to acetyl-CoA. 

Normally, acetyl-CoA carboxylase exists in the cytosol as an inactive protomer, Mr = 2 x 105. Citrate induces polymerization of the protomer into long filaments of an active, multifunctional enzyme, Mr = 4.8 x 106. The 

The formation of malonyl-CoA signals the beginning of the synthesis of palmitic acid (C16 ()). This occurs on a multifunctional enzyme complex, the fatty acid synthase. In mammalian liver, the enzyme complex consists of two identical polypeptides, each with specific binding sites for malonyl and alkanoyl groups, and eight different enzyme activities. 

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PPARy is strongly expressed in adipocytes, and stimulation by TZDs promotes adipogenesis, predominantly in preadipocytes from subcutaneous depots. Increased transcription of transporters and enzymes involved in fatty acid uptake and lipogenesis increases the deposition of lipid in these adipocytes (Table 2). This appears to facilitate a reduction in hyperglycaemia by reducing circulating concentrations of non-esterified... 

Biological actions Adipocyte differentiation fatty acid uptake lipogenesis glucose uptake other effects on nutrient metabolism which lower hepatic glucose production... 

The citric acid cycle is the final common pathway for the aerobic oxidation of carbohydrate, lipid, and protein because glucose, fatty acids, and most amino acids are metabolized to acetyl-CoA or intermediates of the cycle. It also has a central role in gluconeogenesis, lipogenesis, and interconversion of amino acids. Many of these processes occur in most tissues, but the hver is the only tissue in which all occur to a significant extent. The repercussions are therefore profound when, for example, large numbers of hepatic cells are damaged as in acute hepatitis or replaced by connective tissue (as in cirrhosis). Very few, if any, genetic abnormalities of citric acid cycle enzymes have been reported such ab-normahties would be incompatible with life or normal development. 

Both dehydrogenases of the pentose phosphate pathway can be classified as adaptive enzymes, since they increase in activity in the well-fed animal and when insulin is given to a diabetic animal. Activity is low in diabetes or starvation. Malic enzyme and ATP-citrate lyase behave similarly, indicating that these two enzymes are involved in lipogenesis rather than gluconeogenesis (Chapter 21). 

The pathway has an oxidative phase, which is irreversible and generates NADPH and a nonoxidative phase, which is reversible and provides ribose precursors for nucleotide synthesis. The complete pathway is present only in those tissues having a requirement for NADPH for reductive syntheses, eg, lipogenesis or steroidogenesis, whereas the nonoxidative phase is present in all cells requiring ribose. 

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... 

The Main Source of NADPH for Lipogenesis Is the Pentose Phosphate Pathway... 

Figure21-4. The provision of acetyl-CoA and NADPH for lipogenesis. (PPP, pentose phosphate pathway T, tricarboxylate transporter K, a-ketoglutarate transporter P, pyruvate transporter.)...

SHORT- LONG-TERM MECHANISMS REGULATE LIPOGENESIS... 

Acetyl-CoA Carboxylase Is the Most Important Enzyme in the Regulation of Lipogenesis... 

Insulin Also Regulates Lipogenesis by Other Mechanisms... 

Insulin stimulates lipogenesis by several other mechanisms as well as by increasing acetyl-CoA carboxylase activity. It increases the transport of glucose into the cell (eg, in adipose tissue), increasing the availability of both pyruvate for fatty acid synthesis and glycerol 3-phosphate for esterification of the newly formed fatty acids, and also converts the inactive form of pyruvate dehydrogenase to the active form in adipose tissue but not in liver. Insulin also—by its ability to depress the level of intracellular cAMP—inhibits lipolysis in adipose tissue and thereby reduces the concentration of... 

The synthesis of long-chain fatty acids (lipogenesis) is carried out by two enzyme systems acetyl-CoA carboxylase and fatty acid synthase. 

Lipogenesis is regulated at the acetyl-CoA carboxylase step by allosteric modifiers, phosphorylation/de-phosphorylation, and induction and repression of enzyme synthesis. Citrate activates the enzyme, and long-chain acyl-CoA inhibits its activity. Insulin activates acetyl-CoA carboxylase whereas glucagon and epinephrine have opposite actions. 

Human adipose tissue may not be an important site of lipogenesis. There is no significant incorporation of glucose or pyruvate into long-chain fatty acids ATP-... 

Adipose tissue Storage and breakdown of triacylglyc-erol Esterification of fatty acids and lipolysis lipogenesis Glucose, lipoprotein triacylglycerol Free fatty acids, glycerol Lipoprotein lipase, hormone-sensitive lipase... 

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