Liver glucagon

Figure 4.17 cAMP activation of glycogen phosphorylasein liver. Glucagon stimulation of liver cells... 

COMPOUNDS ACTING IN THE LIVER Glucagon secretion inhibitors Somatostatin analogues Fatty acid oxidation inhibitors CPTI inhibitors... 

Glucagon is processed by the pancreatic islets in response to low blood glucose level. In the liver, glucagon binds to a membrane receptor coupled to GTP-bonding proteins, inducing an intracellular rise in cAMP, which subsequently activates the Protein kinase A (PKA) and downstream effectors. 

In the liver, glucagon increases cyclic AMP (cAMP) levels, as schematized in Figure 23.3. The resultant metabolic cascades, discussed in Chapters 13 (here) and 16 (here), promote giycogenolysis and inhibit glycogen synthesis. In addition, by activating the hydrolysis of fructose-2,6-bisphosphate, cAMP inhibits glycolysis and activates gluconeogenesis (see here). 

Glucagon stimulates gluconeogenesis and insulin slows it down. In perfused liver glucagon stimulates gluconeogenesis from pyruvate, lactate, and oxaloace-tate (but not from alanine). Crossover studies have established that glucagon acts on gluconeogenesis by activating pyruvic carboxylase. 

Pyruvate kinase possesses allosteric sites for numerous effectors. It is activated by AMP and fructose-1,6-bisphosphate and inhibited by ATP, acetyl-CoA, and alanine. (Note that alanine is the a-amino acid counterpart of the a-keto acid, pyruvate.) Furthermore, liver pyruvate kinase is regulated by covalent modification. Flormones such as glucagon activate a cAMP-dependent protein kinase, which transfers a phosphoryl group from ATP to the enzyme. The phos-phorylated form of pyruvate kinase is more strongly inhibited by ATP and alanine and has a higher for PEP, so that, in the presence of physiological levels of PEP, the enzyme is inactive. Then PEP is used as a substrate for glucose synthesis in the pathway (to be described in Chapter 23), instead... 

Glucagon is secreted as a response to hypoglycemia and activates both glycogenolysis and gluconeogenesis in the liver, causing release of glucose into the blood. 

In adipose tissue, the effect of the decrease in insulin and increase in glucagon results in inhibition of lipo-genesis, inactivation of lipoprotein lipase, and activation of hormone-sensitive lipase (Chapter 25). This leads to release of increased amounts of glycerol (a substrate for gluconeogenesis in the liver) and free fatty acids, which are used by skeletal muscle and liver as their preferred metabolic fuels, so sparing glucose. 

Glucagon Gs-cAMP-A kinase glycogen breakdown (muscle), gluconeogenesis (liver)... 

Primary signals Insulin turns off. Glucagon turns on. Acetyl-CoA turns on. Phosphorylation turns on in liver. 

---