Increased (induction of) or decreased (repression of) enzyme synthesis leads to changes in the number of enzyme molecules, rather than changing the activity of existing enzyme molecules. Enzymes subject to synthesis regulation are often those that are needed under specific physiologic conditions. For example, in the well-fed state, elevated insulin levels result in an increase in the synthesis of key enzymes, such as acetyl coenzyme A (CoA) carboxylase (ACC) and fatty acid synthase (see p. 313), involved in anabolic metabolism. In the fasted state, glucagon induces expression of phosphoenolpyruvate carboxykinase (PEPCK) of gluconeogenesis (see p. 314). [Note: Both hormones affect gene transcription.]
III. LIVER: NUTRIENT DISTRIBUTION CENTER
The liver is uniquely situated to process and distribute dietary nutrients because the venous drainage of the gut and pancreas passes through the hepatic portal vein before entry into the general circulation. Thus, after a meal, the liver is bathed in blood containing absorbed nutrients and elevated levels of insulin secreted by the pancreas. During the absorptive period, the liver takes up carbohydrates, lipids, and most amino acids. These nutrients are then metabolized, stored, or routed to other tissues. In this way, the liver smooths out potentially broad fluctuations in the availability of nutrients for the peripheral tissues.
A. Carbohydrate metabolism
The liver is normally a glucose-producing rather than a glucose-using organ. However, after a meal containing carbohydrate, the liver becomes a net consumer, retaining roughly 60 g of every 100 g of glucose presented by the portal system. This increased use reflects increased glucose uptake by the hepatocytes. Their insulin-independent glucose transporter (GLUT 2) has a low affinity (high Km [Michaelis constant]) for glucose and, therefore, takes up glucose only when blood glucose is high (see p. 98).
Processes that are upregulated when hepatic glucose is increased include the following.
1. Increased glucose phosphorylation: The elevated levels of glucose within the hepatocyte (as a result of elevated extracellular levels) allow glucokinase to phosphorylate glucose to glucose 6-phosphate (Fig. 24.3, ). [Note: Glucokinase has a high Km for glucose, is not subject to direct product inhibition, and has a sigmoidal reaction curve (see p. 98).] 2.
Increased glycogenesis: The conversion of glucose 6-phosphate to glycogen is favored by the activation of glycogen synthase, both by dephosphorylation and by increased availability of glucose 6-phosphate, its positive allosteric effector (see Fig. 24.3, ).
3.
Increased pentose phosphate pathway activity: The increased availability of glucose 6-phosphate, combined with the active use of nicotinamide adenine dinucleotide phosphate (NADPH) in hepatic lipogenesis, stimulates the pentose phosphate pathway (see p. 145). This pathway typically accounts for 5%–10% of the glucose metabolized by the liver (see Fig. 24.3, ).
4.