See Section B.2 for an explanation of the decline in gluconeogenesis.] 2. Increased gluconeogenesis: The synthesis of glucose and its release into the circulation are vital hepatic functions during short-and long-term fasting (see Fig. 24.12, ). The carbon skeletons for gluconeogenesis are derived primarily from glucogenic amino acids and lactate from muscle and glycerol from adipose tissue. Gluconeogenesis, favored by activation of fructose 1,6-bisphosphatase (because of decreased availability of its inhibitor fructose 2,6-bisphosphate; see p. 121) and by induction of PEPCK by glucagon (see p. 122), begins 4–6 hours after the last meal and becomes fully active as stores of liver glycogen are depleted (see Fig. 24.11). [Note: The decrease in fructose 2,6-bisphosphate simultaneously inhibits glycolysis at PFK-1 (see p. 99).]
B. Fat metabolism 1. Increased fatty acid oxidation: The oxidation of FA obtained from TAG hydrolysis in adipose tissue is the major source of energy in hepatic tissue in the fasted state (see Fig. 24.12, ). The fall in malonyl CoA because of phosphorylation (inactivation) of ACC by AMPK removes the brake on CPT-I, allowing β-oxidation to occur (see p. 191). FA oxidation generates NADH, flavin adenine dinucleotide (FADH2), and acetyl CoA.
The NADH inhibits the TCA cycle and shifts OAA to malate. This results in acetyl CoA being available for ketogenesis. The acetyl CoA is also an allosteric activator of PC and an allosteric inhibitor of PDH, thereby favoring use of pyruvate in gluconeogenesis (see Fig. 10.9, p. 122). [Note: Acetyl CoA cannot be used as a substrate for gluconeogenesis, in part because the PDH reaction is irreversible.] Oxidation of NADH and FADH2 coupled with oxidative phosphorylation supplies the energy required by the PC and PEPCK reactions of gluconeogenesis.
2. Increased ketogenesis: The liver is unique in being able to synthesize and release ketone bodies, primarily 3-hydroxybutyrate but also acetoacetate, for use as fuel by peripheral tissues but not by the liver itself because liver lacks thiophorase (see p. 197). Ketogenesis, which starts during the first days of fasting (Fig. 24.13), is favored when the concentration of acetyl CoA from FA oxidation exceeds the oxidative capacity of the TCA cycle. [Note: Ketogenesis releases CoA, insuring its availability for continued FA oxidation.] The availability of circulating water-soluble ketone bodies is important in fasting because they can be used for fuel by most tissues, including the brain, once their blood level is high enough. Ketone body concentration in blood increases from ~50 µM to ~6 mM in fasting. This reduces the need for gluconeogenesis from amino acid carbon skeletons, thus preserving essential protein (see Fig. 24.11). Ketogenesis as part of the overall hepatic response to fasting is shown in Figure 24.12, . [Note: Ketone bodies are organic acids and, when present at high concentrations, can cause ketoacidosis.]
IX.
A.
Glucose transport by insulin-sensitive GLUT-4 into the adipocyte and its subsequent metabolism are decreased because of low levels of circulating insulin. This results in decreased TAG synthesis.
B. Fat metabolism 1.