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Citrate <

ATP:citrate lyase

Citrate <

Glucose Insulin +) Glycolysis

Pyruvate Pyruvatl^A PC^ PDHU- Insulin y

HMG-CoA

Pyruvate Pyruvatl^A PC^ PDHU- Insulin

OAA Acety-CoA

"V"c/frafe T synthase Citrate - -

Mitochondrion

Insulin +| Cholesterol

Fig. 4.3.1 Note: Small molecules such as CO2, ATP, NAD+/NADH and NADP+/NADPH are not shown.

ISI3

The first 'committed' step is the synthesis of cytosolic HMG-CoA, but an important regulatory step (and a target for drug action; see Section 9.4.2.1) is the reduction of HMG-CoA by HMG-CoA reductase.

Other abbreviations: ACC, acetyl-CoA carboxylase; OAA, oxaloacetate; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase.

Regulation

The activity of several steps in the pathway of fatty acid synthesis is increased acutely by insulin (shown as insulin +) and in addition the expression of the enzymes marked * is increased by insulin (longer-term regulation). NADPH is required for fatty acid synthesis. This comes both from the pentose phosphate pathway (Section 4.1.2.1) and from the enzyme responsible for conversion of cytosolic malate to pyruvate (see Fig. 4.3.1), malate dehydrogenase (oxalo-acetate-decarboxylating) (NADP+), commonly called malic enzyme. Expression of malic enzyme, like that of glucose-6-phosphate dehydrogenase (see Pentose phosphate pathway, Section 4.1.2.1), is increased by carbohydrate availability, and also by increased stability of its mRNA. In the pathway of cholesterol synthesis, HMG-CoA reductase is regulated by reversible phosphorylation and activated acutely by insulin. It is also subject to longer-term regulation by the SREBP system as described in Section 2.4.2.3 and later in Box 9.3.

special role in amino acid oxidation, not least because it is the organ that first receives the dietary amino acids, which enter the circulation via the portal vein. It is also the only organ capable of eliminating the nitrogen from amino acids, by synthesising urea. Therefore, with a few exceptions, amino acid catabolism occurs predominantly in the liver. (An important exception is that of the group of branched chain amino acids, whose catabolism is largely initiated in muscle; see Section 6.3.2.2.) Amino acid oxidation provides about half the liver's energy requirements. Figure 4.6 provides a general overview of hepatic amino acid metabolism.

Amino acids are not merely substrates for energy production in the liver, however. They also provide a substrate for synthesis of glucose (particularly alanine - see Box 4.2), of fatty acids and of ketone bodies. Of course, amino acids also serve as precursors for hepatic protein synthesis: both proteins required within the liver, and proteins exported into the circulation such as albumin.

An important general reaction in amino acid catabolism is the loss of the amino group by the process of transamination (Fig. 4.6), described in detail later (Box 6.2). The 2-oxoacid (or keto acid) resulting may enter a catabolic or an anabolic pathway directly: for instance, the 2-oxoacid of alanine is pyru-vate, the end-product of glycolysis; that of glutamic acid is 2-oxoglutarate,

Amino acid

Transporter

Protein degradation Glucagon

Amino acid Urea c/c/e

LgiutamateJ

CO2 - Acetyi-CoA <— Pyruvate/TCA cycle intermediate

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