Principles of Biochemistry, Volume 3 - A. Lehninger 1985

Selected Aspects of Human Biochemistry
Digestion, Nutrient Transport, and Metabolic Interrelationships
The liver possesses five distinct pathways of sugar metabolism

Most of the free D-glucose taken up by the Liver is phosphorylated by ATP to form glucose-6-phosphate. The D-fructose, D-galactose, and D-mannose absorbed in the Small Intestine are also converted into D-glucose-6-phosphate via the enzymatic pathway discussed previously (Sec. 15.9). D-glucose-6-phosphate thus lies at the crossroads of all carbohydrate Metabolic Pathways in the liver. The METABOLISM of this compound in the liver can proceed via five main directions, and the Selection of any particular pathway depends on the hourly or even minutely fluctuating "supply and demand" (Fig. 24-9).

a. Conversion into Blood glucose

Glucose-6-phosphate can be dephosphorylated by glucose-6-phosphatase to yield free D-glucose, which enters the bloodstream and is delivered to other Tissues. This pathway of glucose-6-phosphate metabolism is of paramount importance because blood glucose concentration must be maintained at a sufficiently high level to provide energy for the Brain and other tissues.

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Fig. 24-9. PATHWAYS OF GLUCOSE-6-phosphate metabolism in the liver. Here, as in Figs. 24-10 and 24-11, biosynthetic pathways are indicated by upward-pointing arrows, degradative pathways by downward-pointing arrows, and distribution to other Organs by horizontal arrows.

b. Conversion into Glycogen

The amount of glucose-6-phosphate not utilized for immediate conversion into blood glucose is converted into glycogen through the sequential action of phosphoglucomutase and glycogen synthase (Sec. 20.13).

c. Conversion into Fatty acids and Cholesterol

Excess glucose-6-phosphate not used for The production of blood glucose or liver glycogen is broken down via Glycolysis and the subsequent action of Pyruvate dehydrogenase to acetyl-CoA, which is converted into malonyl-CoA and further into fatty acids (Sec. 21.7). These Fatty acids are used to synthesize triacylglycerols and Phospholipids (Sec. 21.8), which are partially exported to other tissues via plasma Lipoproteins. A certain fraction of hepatic acetyl-CoA is channeled into cholesterol synthesis (Sec. 21.16).

d. Oxidative degradation to CO₂

The acetyl-CoA derived from glucose-6-phosphate via glycolysis and subsequent pyruvate decarboxylation can be oxidized in The Citric Acid Cycle. Subsequent Electron Transport and Oxidative Phosphorylation lead to the generation of energy in the form of ATP. However, under normal conditions, the liver relies primarily on fatty acids for oxidation in The Citric Acid cycle.

e. Degradation via the Pentose Phosphate Pathway

Glucose-6-phosphate serves as a substrate for The pentose phosphate pathway, which yields: 1) NADPH as a reducing agent required for the reductive steps of Fatty acid and Cholesterol Biosynthesis (Sec. 21.5), and 2) D-ribose-5-phosphate, a precursor for nucleotide biosynthesis (Sec. 16.13).

Under the action of various regulatory Enzymes and Hormones (Chap. 25), the liver distributes the flux of glucose residues among the aforementioned pathways depending on the balance between the body's metabolic demands and dietary carbohydrate intake.