Nutrients refer to substances that provide nourishment essential for the maintenance of life and for growth. During digestion in mammals, the three main classes of nutrients (carbohydrates, proteins, and fats) undergo enzymatic hydrolysis into their simple constituents. This breakdown is necessary because the epithelial cells lining the intestinal lumen absorb only relatively small molecules.
Many of the fatty acids and monoacylglycerols released by digestion of fats in the intestine are reassembled within these epithelial cells into triacylglycerols (TAGs). After being absorbed, most sugars and amino acids and some TAGs travel in the bloodstream to the liver;
the remaining TAGs enter adipose tissue via the lymphatic system. The portal vein is a direct route from the digestive organs to the liver, and liver therefore has first access to ingested nutrients. The kinds and amounts of nutrients supplied to the liver vary with several factors, including the diet and the time between meals. The demand of extrahepatic tissues for fuels and precursors varies among organs and with the level of activity and overall nutritional state of the individual. To meet these changing circumstances, the liver has remarkable metabolic flexibility. For example, when the diet is rich in protein, hepatocytes supply themselves tissues also can adjust their metabolism to prevailing conditions, but none is as adaptable as the liver, and none is so central to the organism’s overall metabolism.
The glucose transporter in hepatocytes (GLUT2) is so effective that the concentration of glucose within a hepatocyte is essentially the same as that in the blood. Glucose entering hepatocytes is phosphorylated by hexokinase IV (glucokinase) to yield glucose 6-phosphate.
Glucokinase has a much higher Km for glucose (10 mM) than do the hexokinase isozymes in other cells and, unlike these other isozymes, it is not inhibited by its product, glucose 6-phosphate. The presence of glucokinase allows hepatocytes to continue phosphorylating glucose when the glucose concentration rises well above levels that would overwhelm other hexokinases. The high Km of glucokinase also ensures that the phosphorylation of glucose in hepatocytes is minimal when the glucose concentration is low, preventing the liver from consuming glucose as fuel via glycolysis. This spares glucose for other tissues. Fructose, galactose, and mannose, all absorbed from the small intestine, are also converted to glucose 6-phosphate by enzymatic pathways.
Glucose 6-phosphate is at the crossroads of carbohydrate metabolism in the liver. It may take any of several major metabolic routes depending on the current metabolic needs of the organism. By the action of various allosterically regulated enzymes, and through hormonal regulation of enzyme synthesis and activity, the liver directs the flow of glucose into one or more of these pathways:-
(1) Glucose 6-phosphate is dephosphorylated by glucose 6-phosphatase to yield free glucose which is exported to replenish blood glucose. Export is the predominant pathway when glucose 6-phosphate is in limited supply, because the blood glucose concentration must be kept sufficiently high (4 mM) to provide adequate energy for the brain and other tissues.
(2) Glucose 6-phosphate not immediately needed to form blood glucose is converted to liver glycogen, or it has one of several other fates. Following glucose 6-phosphate breakdown by glycolysis and decarboxylation of the pyruvate (by the pyruvate dehydrogenase reaction),
(3) The acetyl-CoA so formed can be oxidized for energy production by the citric acid cycle, with ensuing electron transfer and oxidative phosphorylation yielding ATP. (Normally, however, fatty acids are the preferred fuel for energy production in hepatocytes.)
(4) Acetyl- CoA can also serve as the precursor of fatty acids, which are incorporated into TAGs and phospholipids, and cholesterol. Much of the lipid synthesized in the liver is transported to other tissues by blood lipoproteins.
(5) Finally, glucose 6-phosphate can enter the pentose phosphate pathway, yielding both reducing power (NADPH), needed for the biosynthesis of fatty acids and cholesterol, and D-ribose 5-phosphate, a precursor for nucleotide biosynthesis. NADPH is also an essential cofactor in the detoxification and elimination of many drugs and other xenobiotics metabolized in the liver.
