Tissue-Specific Metabolism: The Division of Labor:- The Liver Processes and Distributes Nutrients
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 re assembled 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 lym phatic 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 liver has two main cell types. Kupffer cells are phagocytes, important in immune function. Hepatocytes, of primary interest here, transform dietary nutrients into the fuels and precursors required by other tissues and export them via the blood. 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 with high levels of enzymes for amino acid catabolism and gluconeogenesis. Within hours after a shift to a high carbohydrate diet, the levels of these enzymes begin to drop and the hepatocytes increase their synthesis of en zymes essential to carbohydrate metabolism and fat syn thesis. Liver enzymes turn over (are synthesized and degraded) at five to ten times the rate of enzyme turnover in other tissues, such as muscle. Extrahepatic 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. What follows is a survey of the possible fates of sugars, amino acids, and lipids that enter the liver from the bloodstream. To help you recall the metabolic transformations discussed here, Table 23–2shows the major pathways and processes to which we refer and indicates by figure number where each pathway is presented in detail. Here, we present summaries of the pathways, referring to the step numbers in Figures 23–13 to 23–15. Sugars 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 examined in Chapter 14. Glucose 6-phosphate is at the crossroads of carbohydrate metabolism in the liver. It may take any of several major metabolic routes (Fig. 23–13), 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.
FIGURE 23–13 Metabolic pathways for glucose 6-phosphate in the liver. Here and in Figures 23–14 and 23–15, anabolic pathways are shown leading upward, catabolic pathways leading downward, and distribution to other organs horizontally. The numbered processes in each figure are described in the text.
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 co factor in the detoxification and elimination of many drugs and other xenobiotics metabolized in the liver. Amino Acids Amino acids that enter the liver follow several important metabolic routes . 1 . The liver constantly renews its own proteins, which have a relatively high turnover rate (average half-life of only a few days), and is also the site of biosynthesis of most plasma proteins. 2 Alternatively, amino acids pass in the bloodstream to other organs, to be used in the synthesis of tissue proteins. 3 Other amino acids are precursors in the biosynthesis of nucleotides, hormones, and other nitrogenous compounds in the liver and other tissues. 4a Amino acids not needed as biosynthetic precursors are transaminated or deaminated and degraded to yield pyruvate and citric acid cycle intermediates, with various fates; 4b the ammonia released is converted to the excretory product urea. 5 Pyruvate can be con verted to glucose and glycogen via gluconeogenesis or 6 it can be converted to acetyl-CoA, which has several possible fates. 7 It can be oxidized via the citric acid cycle and 8 oxidative phosphorylation to produce ATP, or 9 converted to lipids for storage. 10 Citric acid cy cle intermediates can be siphoned off into glucose syn thesis by gluconeogenesis. The liver also metabolizes amino acids that arrive intermittently from other tissues. The blood is adequately supplied with glucose just after the digestion and ab sorption of dietary carbohydrate or, between meals, by the conversion of liver glycogen to blood glucose. During the interval between meals, especially if prolonged, some muscle protein is degraded to amino acids. These amino acids donate their amino groups (by transamination) to pyruvate, the product of glycolysis, to yield alanine, which 11 is transported to the liver and deaminated. Hepatocytes convert the resulting pyruvate to blood glucose (via gluconeogenesis 5), and the ammonia to urea for excretion. One benefit of this glucose-alanine cycle is the smoothing out of fluctuations in blood glucose between meals. The amino acid deficit incurred in the muscles is made up after the next meal by incoming dietary amino acids.
The fatty acid components of the lipids entering hepatocytes also have several different fates (Fig. 23–15). 1 Some are converted to liver lipids. 2 Under most circumstances, fatty acids are the primary oxidative fuel in the liver. Free fatty acids may be activated nd oxidized to yield acetyl-CoA and NADH. 3 and 4 The acetyl-CoA is further oxidized via the citric acid cycle, and the oxidations in the cycle drive the synthesis of ATP by oxidative phosphorylation. 5 Excess acetyl CoA released by oxidation of fatty acids and not required by the liver is converted to the ketone bodies, acetoacetate and -hydroxybutyrate; these circulate in the blood to other tissues, to be used as fuel for the citric acid cycle. Ketone bodies may be regarded as a transport form of acetyl groups. They can supply a significant fraction of the energy in some extrahepatic tissues—up to one third in the heart, and as much as 60% to 70% in the brain during prolonged fasting. 6 Some of the acetyl CoA derived from fatty acids (and from glucose) is used for the biosynthesis of cholesterol, which is required for membrane synthesis. Cholesterol is also the precursor of all steroid hormones and of the bile salts, which are essential for the digestion and absorption of lipids. The final two metabolic fates of lipids involve specialized mechanisms for the transport of insoluble lipids in the blood. 7 Fatty acids are converted to the phospholipids and TAGs of plasma lipoproteins, which carry lipids to adipose tissue for storage as TAGs. 8 Some free fatty acids become bound to serum albumin and are carried to the heart and skeletal muscles, which absorb and oxidize free fatty acids as a major fuel. Serum albumin is the most abundant plasma protein; one molecule of serum albumin can carry up to 10 molecules of free fatty acid to the tissues where the fatty acids are released and consumed. The liver thus serves as the body’s distribution center, exporting nutrients in the correct proportions to other organs, smoothing out fluctuations in metabolism caused by intermittent food intake, and processing excess amino groups into urea and other products to be disposed of by the kidneys. Certain nutrients are stored in the liver, including Fe ions and vitamin A. The liver also detoxifies foreign organic compounds, such as drugs, food additives, preservatives, and other possibly harmful agents with no food value. Detoxification often involves the cytochrome P-450–dependent hydroxylation of relatively insoluble organic compounds, making them sufficiently soluble for further breakdown and excretion (see Box 21–1).
