Lipogenesis enzymes

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... 

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). 

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

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. 

Very little data are available regarding effects of anabolic steroid implants on the lipid metabolism in growing ruminants. Lipogenic enzyme activity and fatty acid synthesis in vitro were elevated in subcutaneous adipose tissue from bulls implanted with estradiol (44), which may account for the increase in fat content of carcasses reported in some studies. TBA implants have no effect on lipogenesis in intact heifers, and only tend to reduce lipogenic enzyme activities in ovariectomized heifers (45). 

Increased levels of apolipoproteins and rate-limiting enzymes of lipogenesis and their mRNAs have been demonstrated in the liver of nephrotic rats (V5), although increased liver cholesterol synthesis has not been confirmed in nephrotic patients (D9). Cholesterol synthesis in the liver probably does not change during antipro-teinuric treatment (D9). The rate of synthesis of LDL apoprotein B is variable and depends on the presence or absence of hypertriglyceridemia (V6). 

It is worth noting that hypothyroidism also leads to an increased lipogenesis in the adipocyte which is independent of cyclic AMP [86,87]. In other words, the activity of several enzymes of the lipogenic pathway are stimulated in hypothyroidism independently from the effects of T3 on the cyclic AMP system. 

Figure 2.4. The provision of acetyl-CoA and NADPH for lipogenesis. PPP, pentose phosphate pathway T, tricarboxylate transporter K, a-ketoglutarate transporter. In ruminants, pyruvate dehydrogenase, ATP-citrate lyase and malic enzyme activities are low and perhaps non-functional. (From Murray et al., 1988. Harper s Biochemistry, 21st edn, p. 207, Appleton and Lange, Norwalk, CT reproduced with permission of The McGraw-Hill Companies).

Williamson, D.H., Munday, M.R., Jones, R.G., Roberts, A.F., Ramsey, A.J. 1983. Short-term dietary regulation of lipogenesis in the lactating mammary gland of the rat. Adv. Enzyme Regul. 21, 135-145. 

Incubation of hepatocytes with glucagon also increases the phosphorylation of another lipogenic enzyme ATP-citrate lyase [127,128], The purified enzyme is also phosphorylated by cAMP-dependent protein kinase in vitro [128,129] resulting in a 2-fold increase in the Km for ATP [130], However, it is unclear what role this plays in the inhibition of lipogenesis. 

Takahashi et al. (2003) previously demonstrated that CLA increases the activity and mRNA levels of hepatic lipogenic enzymes they suggested that enhanced lipogenesis is a principal mechanism of CLA-induced hepatic steatosis in mice. In this study, suppression of the activity and mRNA expression... 

Regulation of Pyruvate Dehydrogenase Activity Pyruvate dehydrogenase is the key enzyme that commits pyruvate (and hence the products of carbohydrate metabolism) to complete oxidation (via the tricarboxyUc acid cycle) or lipogenesis. It is subject to regulation by both product inhibition and a phosphorylation/dephosphorylation mechanism. Acetyl CoA and NADH are both inhibitors, competing with coenzyme A and NAD+. 

MetabolicaUy, biotin is of central importance in lipogenesis, gluconeogen-esis, and the catabolism of branched-chain (and other) amino acids. There are two well-characterized biotin-responsive inborn errors of metabolism, which are fatal if untreated holocarboxylase synthetase deficiency and biotinidase deficiency. In addition, biotin induces a number of enzymes, including glu-cokinase and other key enzymes of glycolysis. Biotinylation of histones may be important in regulation of the cell cycle. 

There are no unequivocal reports of acetyl CoA carboxylase deficiency presumably impairment of this key enzyme in lipogenesis would not be compatible with intrauterine development. 

Lipogenesis, the synthesis of lipids from carbohydrate via acetyl-CoA, occurs almost exclusively in the liver cells and the fatty tissue, (s. fig. 3.9) According to lipid topogenesis (4), the enzymes involved in triglyceride and phospholipid synthesis are localized on the cytoplasmic surface of the endoplasmic reticulum. The level of hepatic synthesis is regulated primarily by the insulin-glucagon quotient, as described by R.H. Unger in 1971. 

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