In fasting (as in the well-fed state), the flow of intermediates through the pathways of energy metabolism is controlled by four mechanisms: 1) the availability of substrates, 2) allosteric regulation of enzymes, 3) covalent modification of enzymes, and 4) induction-repression of enzyme synthesis. The metabolic changes observed in fasting are generally opposite those described for the absorptive state (see Fig. 24.9). For example, although most of the enzymes regulated by covalent modification are dephosphorylated and active in the well-fed state, they are phosphorylated and inactive in the fasted state. Three exceptions are glycogen phosphorylase (see p. 132), glycogen phosphorylase kinase (see p. 132), and HSL (see p. 189), which are active in their phosphorylated states. In fasting, substrates are not provided by the diet but are available from the breakdown of stores and/or tissues, such as glycogenolysis with release of glucose from the liver, lipolysis with release of FA and glycerol from TAG in adipose tissue, and proteolysis with release of amino acids from muscle. Recognition that the changes in fasting are the reciprocal of those in the fed state is helpful in understanding the ebb and flow of metabolism.
VIII. LIVER IN FASTING
The primary role of the liver in fasting is maintenance of blood glucose through the production of glucose (from glycogenolysis and gluconeogenesis) for glucose-requiring tissues and the synthesis and distribution of ketone bodies for use by other tissues. Therefore, hepatic metabolism is distinguished from peripheral (or extrahepatic) metabolism.
A. Carbohydrate metabolism
The liver first uses glycogen degradation and then gluconeogenesis to maintain blood glucose levels to sustain energy metabolism of the brain and other glucose-requiring tissues in the fasted state. [Note: Recall that the presence of glucose-6-phosphatase in the liver allows the production of free glucose both from glycogenolysis and from gluconeogenesis (see Fig. 24.4).] 1. Increased glycogenolysis: Figure 24.11 shows the sources of blood glucose after ingestion of 100 g of glucose. During the brief absorptive period, ingested glucose is the major source of blood glucose. Several hours later, blood glucose levels have declined sufficiently to cause increased secretion of glucagon and decreased secretion of insulin. The increased glucagon/insulin ratio causes a rapid mobilization of liver glycogen stores (which contain ~80 g of glycogen in the fed state) because of PKA-mediated phosphorylation (and activation) of glycogen phosphorylase kinase that phosphorylates (and activates) glycogen phosphorylase (see p. 132). Figure 24.11 shows that because liver glycogen is exhausted by 24 hours of fasting, hepatic glycogenolysis is a transient response to early fasting. Figure 24.12, , shows glycogen degradation as part of the overall metabolic response of the liver during fasting. [Note: Phosphorylation of glycogen synthase simultaneously inhibits glycogenesis.]