Lipogenesis, NADPH

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. 

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.)...

Increased activity of the hexose monophosphate pathway (HMP) The increased availability of glucose 6-phosphate in the well-fed state, combined with the active use of NADPH in hepatic lipogenesis, stimulate the HMP (see Chapter 12, p. 143). This pathway typically accounts for five to ten percent of the glucose metabolized by the liver (see Figure 24.3, ). 

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).

Transketolase is involved in the pentose phosphate pathway, which is the major pathway of carbohydrate metaholism in some tissues and a significant alternative to glycolysis in all tissues. The main importance of the pentose phosphate pathway is in the production of NADPH for use in hiosynthetic reactions (and especially lipogenesis) and the de novo synthesis of rihose for nucleotide synthesis. 

In general, NAD+ is involved as an electron acceptor in energy-yielding metabolisni, and the resultant NADH is oxidized by the mitochondrial electron transport chain. The major coenzyme for reductive synthetic reactions is NADPH. An exception here is the pentose phosphate pathway (see Figure 6.4), which reduces NADP+ to NADPH and is the source of about half the reductant for lipogenesis. 

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. 

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. 

The main control of flux in the oxidative pentose phosphate pathway under normal conditions is the profound product inhibition by NADPH on the first enzyme, glucose-6-phosphate dehydrogenase (G6PDH). NADPH concentrations can become low due to active lipogenesis. Then G6PDH will increase in activity. 

It is generally accepted that only NADPH would be able to supply the hydrogen necessary for lipogenesis in the condensation system (Lynen, 1961 Ball, 1966). Lowenstein, therefore, has suggested another pathway for the formation of NADPH in the cytoplasm (Lowenstein, 1961b). It is dependent on the capacity of the cytoplasm to accomplish the first reactions of the tricarboxylic cycle, i.e., the reactions that yield a-ketoglutaric acid. A cytoplasmic NADP-isocitrate dehydrogenase, in contrast to the mitochondrial enzyme, the coen-... 

In liver, the enzymes of the oxidative pathway exert, in comparison with adipose tissue, lower activity (Weber, 1963) consequently the malate, and also the citrate, pathways become more important in supplying hydrogen for lipogenesis. Malate difihises easily out of the mitochondria, therefore, favoring NADH transfer from mitochondria to cytoplasm and providing NADPH via the malic enzyme (Krebs et al., 1967). 

A limited number of studies concerning the 3- H and 4- H glucose incorporation have been published as their preparation is difiBcult. Rognstad and Katz (1969) synthesized these precursors to study their incorporation into liver slices and rat adipose tissue. From their results it follows (1) All the NADPH generated by the pentose cycle is utilized for lipogenesis (Katz et al., 1965). (2) Incorporation of glu-cose-3- H into fatty acids is approximately twice as high as that of -1- H, which is probably due to isotopic discrimination (Katz and Rognstad, 1966). 

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