Question

1) Describe in detail how the liver regulates both glycolysis and gluconeogenesis?

2) Please explain how the same enzymes within glycolysis and gluconeogenesis are used for both pathways?

Answer 1

1)

Liver can both produce and consume carbohydrate, allowing it to regulate blood glucose concentration in a narrow physiologic range regardless of feeding or exercise status. Hepatic glucose production protects from hypoglycemia, is essential for life, and except for periods of feeding, is almost constitutively active. Hepatic glucose production is supported by glycogen degradation (glycogenolysis) and new synthesis (gluconeogenesis), which it performs by converting circulating metabolites like lactate, amino acids and glycerol to glucose. Recent development of molecular biology and gene analysis has revealed the precise molecular mechanism of hepatic carbohydrate metabolism and regulatory system is with the help of endocrine system, insulin or glucagon signaling pathway and those hormone-induced transcription of effector molecules, CREB, FoxO1, ChREBP, SREBPs, PGC1 or several kinds of enzymes.

During feeding, the liver protects against hyperglycemia by taking up glucose to restore glycogen or to make lipids (lipogenesis). The transformation of liver from a producer to a consumer of glucose is marshaled by insulin, glucagon, and other key hormones that mediate transcription and concentration of enzymes in these pathways, and/or by metabolic mechanisms which change the activity of these enzymes.

2)

Gluconeogenesis and glycolysis are coordinated in such a way so that, when one pathway is relatively inactive while the other is highly active. If both sets of reactions were highly active at the same time, the net result would be the hydrolysis of four nucleotide triphosphates (two ATP plus two GTP) per reaction cycle. Both glycolysis and gluconeogenesis are highly exergonic under cellular conditions. However, the amounts and activities of the distinctive enzymes of each pathway are controlled so that both pathways are not highly active at the same time. The rate of glycolysis is also determined by the concentration of glucose, and the rate of gluconeogenesis by the concentrations of lactate and other precursors of glucose.

Interconversion of fructose 6-phosphate and fructose 1,6-bisphosphate is stringently controlled .AMP stimulates phosphofructokinase, whereas ATP and citrate inhibit it. Fructose 1,6-bisphosphatase, on the other hand, is inhibited by AMP and activated by citrate. A high level of AMP indicates that the energy charge is low and signals the need for ATP generation. Conversely, high levels of ATP and citrate indicate that the energy charge is high and that biosynthetic intermediates are abundant. Under these conditions, glycolysis is almost switched off and gluconeogenesis promoted.

Phosphofructokinase and fructose 1,6-bisphosphatase are both reciprocally controlled by fructose 2,6-bisphosphate in the liver . The level of F-2,6-BP is low during starvation and high in the fed state, because of the antagonistic effects of glucagon and insulin on the production and degradation of this signal molecule. Fructose 2,6-bisphosphate strongly stimulates phosphofructokinase and inhibits fructose 1,6-bisphosphatase. Hence, glycolysis is accelerated and gluconeogenesis is diminished when in the fed state. During starvation, gluconeogenesis predominates because the level of F-2,6-BP is very low. Glucose formed by the liver under these conditions is essential for the viability of brain and muscle.

The interconversion of phosphoenolpyruvate and pyruvate also is precisely regulated. High levels of ATP and alanine, which signal that the energy charge is high and that building blocks are abundant, inhibit the enzyme in liver. Conversely, pyruvate carboxylase, which catalyzes the first step in gluconeogenesis from pyruvate, is activated by acetyl CoA and inhibited by ADP. Likewise, ADP inhibits phosphoenolpyruvate carboxykinase. Hence, gluconeogenesis is favored when the cell is rich in biosynthetic precursors and ATP.