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Ch36-Integration of Carbohydrate and Lipid Metabolism 668 36 Integration of Carbohydrate and Lipid Metabolism The purpose of this chapter is to summarize and integrate the major pathways for the utilization of carbohydrates and fats as fuels. We will concentrate on review- ing the regulatory mechanisms that d...

Ch36-Integration of Carbohydrate and Lipid Metabolism
668 36 Integration of Carbohydrate and Lipid Metabolism The purpose of this chapter is to summarize and integrate the major pathways for the utilization of carbohydrates and fats as fuels. We will concentrate on review- ing the regulatory mechanisms that determine the flux of metabolites in the fed and fasting states, integrating the pathways that were described separately under carbohydrate and lipid metabolism. The next section of the book covers the mech- anisms by which the pathways of nitrogen metabolism are coordinated with fat and carbohydrate metabolism. For the species to survive, it is necessary for us to store excess food when we eat and to use these stores when we are fasting. Regulatory mechanisms direct compounds through the pathways of metabolism involved in the storage and uti- lization of fuels. These mechanisms are controlled by hormones, by the concen- tration of available fuels, and by the energy needs of the body. Changes in hormone levels, in the concentration of fuels, and in energy requirements affect the activity of key enzymes in the major pathways of metabo- lism. Intracellular enzymes are generally regulated by activation and inhibition, by phosphorylation and dephosphorylation (or other covalent modifications), by induction and repression of synthesis, and by degradation. Activation and inhibi- tion of enzymes cause immediate changes in metabolism. Phosphorylation and dephosphorylation of enzymes affect metabolism slightly less rapidly. Induction and repression of enzyme synthesis are much slower processes, usually affecting metabolic flux over a period of hours. Degradation of enzymes decreases the amount available to catalyze reactions. The pathways of metabolism have multiple control points and multiple regula- tors at each control point. The function of these complex mechanisms is to pro- duce a graded response to a stimulus and to provide sensitivity to multiple stimuli so that an exact balance is maintained between flux through a given step (or series of steps) and the need or use for the product. Pyruvate dehydrogenase is an example of an enzyme that has multiple regulatory mechanisms. Regardless of insulin levels, the enzyme cannot become fully activated in the presence of products and absence of substrates. The major hormones that regulate the pathways of fuel metabolism are insulin and glucagon. In liver, all effects of glucagon are reversed by insulin, and some of the pathways that insulin activates are inhibited by glucagon. Thus, the pathways of carbohydrate and lipid metabolism are generally regulated by changes in the insulin/glucagon ratio. Although glycogen is a critical storage form of fuel because blood glucose lev- els must be carefully maintained, adipose triacylglycerols are quantitatively the major fuel store in the human. After a meal, both dietary glucose and fat are stored in adipose tissue as triacylglycerol. This fuel is released during fasting, when it provides the main source of energy for the tissues of the body. The length of time we can survive without food depends mainly on the size of our bodies’ fat stores. 669CHAPTER 36 / INTEGRATION OF CARBOHYDRATES AND LIPID METABOLISM Fig. 36.1. Regulation of glucokinase, PFK-1, and pyruvate kinase in the liver. T H E W A I T I N G R O O M Within 2 months of her surgery to remove a benign insulin-secreting � cell tumor of the pancreas, Bea Selmass was again jogging lightly. She had lost the 8 lb that she had gained in the 6 weeks before her surgery. Because her hypoglycemic episodes were no longer occurring, she had no need to eat frequent carbohydrate snacks to prevent the adrenergic and neuroglycopenic symptoms that she had experienced when her tumor was secreting excessive amounts of insulin. A few months after her last hospitalization, Di Abietes was once again brought to the hospital emergency room in diabetic ketoacidosis (DKA). Blood samples for glucose and electrolytes were drawn repeatedly during the first 24 hours. The hospital laboratory reported that the serum in each of these specimens appeared opalescent rather than having its normal clear or transparent appearance. This opalescence results from light scattering caused by the presence of elevated levels of triacylglycerol-rich lipoproteins in the blood When Ann Sulin initially presented with type 2 diabetes mellitus at age 39, she was approximately 30 lb above her ideal weight. Her high serum glucose levels were accompanied by abnormalities in her 14-hour fasting lipid profile. Her serum total cholesterol, low-density lipoprotein (LDL) choles- terol, and triacylglycerol levels were elevated, and her serum high-density lipopro- tein (HDL) cholesterol level was below the normal range. I. REGULATION OF CARBOHYDRATE AND LIPID METABOLISM IN THE FED STATE A. Mechanisms That Affect Glycogen and Triacylglyc- erol Synthesis in Liver After a meal, the liver synthesizes glycogen and triacylglycerol. The level of glyco- gen stored in the liver can increase from approximately 80 g after an overnight fast to a limit of approximately 200–300 g. Although the liver synthesizes triacylglycerol, it does not store this fuel but rather packages it in very-low-density lipoprotein (VLDL) and secretes it into the blood. The fatty acids of the VLDL triacylglycerols secreted from the liver are stored as adipose triacylglycerols. Adipose tissue has an almost infinite capacity to store fat, limited mainly by the ability of the heart to pump blood through the capillaries of the expanding adipose mass. Although we store fat throughout our bodies, it tends to accumulate in places where it does not interfere too much with our mobility: in the abdomen, hips, thighs, and buttocks. Both the synthesis of liver glycogen and the conversion by the liver of dietary glucose to triacylglycerol (lipogenesis) are regulated by mechanisms involving key enzymes in these pathways. 1. GLUCOKINASE After a meal, glucose can be converted to glycogen or to triacylglycerol in the liver. For both processes, glucose is first converted to glucose 6-phosphate by glucoki- nase, a liver enzyme that has a high Km for glucose (Fig. 36.1). Because of the enzyme’s low affinity for glucose, this enzyme is most active in the fed state, when the concentration of glucose is particularly high because the hepatic portal vein + + + – – – – Glucose Glucose-6-P Fructose-1, 6-P Phosphoenolpyruvate ATP ADP glucokinase high Km phosphofructokinase-1 AMP , F-2,6-BP , ATP , Citrate Fructose-6-P pyruvate kinase phosphorylation (cAMP-dependent) Alanine F-1, 6-P Pyruvate 670 SECTION SIX / LIPID METABOLISM carries digestive products directly from the intestine to the liver. Synthesis of glucokinase is also induced by insulin (which is elevated after a meal) and repressed by glucagon (which is elevated during fasting). In keeping with the liver’s function in maintaining blood glucose levels, this system is set up such that the liver can only metabolize glucose when sugar levels are high, and not when sugar levels are low. 2. GLYCOGEN SYNTHASE In the conversion of glucose 6-phosphate to glycogen, the key regulatory enzyme is glycogen synthase. This enzyme is activated by the dephosphorylation that occurs when insulin is elevated and glucagon is decreased (Fig. 36.2) and by the increased level of glucose. 3. PHOSPHOFRUCTOKINASE-1 AND PYRUVATE KINASE For lipogenesis, glucose 6-phosphate is converted through glycolysis to pyruvate. Key enzymes that regulate this pathway in the liver are phosphofructokinase-1 (PFK-1) and pyruvate kinase. PFK-1 is allosterically activated in the fed state by fructose 2,6-bisphosphate and adenosine monophosphate (AMP) (see Fig. 36.1). Phosphofructokinase-2, the enzyme that produces the activator fructose 2,6- bisphosphate, is dephosphorylated and active after a meal (see Chapter 22). Pyru- vate kinase is also activated by dephosphorylation, which is stimulated by the increase of the insulin/glucagon ratio in the fed state (see Fig. 36.1). 4. PYRUVATE DEHYDROGENASE AND PYRUVATE CARBOXYLASE The conversion of pyruvate to fatty acids requires a source of acetyl CoA in the cytosol. Pyruvate can only be converted to acetyl CoA in mitochondria, so it enters mitochondria and forms acetyl CoA through the pyruvate dehydrogenase (PDH) reaction. This enzyme is dephosphorylated and most active when its supply of sub- strates and adenosine diphosphate (ADP) is high, its products are used, and insulin is present (Fig. 36.3). Pyruvate is also converted to oxaloacetate. The enzyme that catalyzes this reac- tion, pyruvate carboxylase, is activated by acetyl CoA. Because acetyl CoA cannot directly cross the mitochondrial membrane to form fatty acids in the cytosol, it con- denses with oxaloacetate, producing citrate. The citrate that is not required for tri- carboxylic acid (TCA) cycle activity crosses the membrane and enters the cytosol. As fatty acids are produced under conditions of high energy, the high NADH/NAD+ ratio in the mitochondria inhibits isocitrate dehydrogenase, which leads to citrate accumulation within the mitochondrial matrix. As the citrate accu- mulates, it is transported out into the cytosol to donate carbons for fatty acid synthesis. 5. CITRATE LYASE, MALIC ENZYME, AND GLUCOSE 6-PHOSPHATE DEHYDROGENASE In the cytosol, citrate is cleaved by citrate lyase, an inducible enzyme, to form oxaloacetate and acetyl CoA (Fig. 36.4). The acetyl CoA is used for fatty acid biosynthesis and for cholesterol synthesis, pathways that are activated by insulin. Oxaloacetate is recycled to pyruvate via cytosolic malate dehydrogenase and malic enzyme, which is inducible. Malic enzyme generates NADPH for the reactions of the fatty acid synthase complex. NADPH is also produced by the two enzymes of the pentose phosphate pathway (see Chapter 29), glucose 6-phosphate dehydroge- nase and 6-phosphogluconate dehydrogenase. Glucose 6-phosphate dehydrogenase is also induced by insulin. glycogen synthase– (inactive) glycogen synthase (active) protein phosphatase protein kinase A Pi PPi UTP ADP ATP Glucagon Glycogen UDP–Glucose Glucose–1–P Glucose–6–P P + Insulin+ Glucose Fig. 36.2. Regulation of glycogen synthase. This enzyme is phosphorylated by a series of kinases, which are initiated by the cAMP- dependent protein kinase, under fasting condi- tions. It is dephosphorylated and active after a meal, and glycogen is stored. Circled P � phosphate; a circled � sign � activated by; a circled � sign � inhibited by. NAD+ NADH pyruvate dehydrogenase inactive pyruvate dehydrogenase active P Pi ADP kinase ADP ATP phosphatase Ca2+ CoASH Pyruvate Acetyl CoA CO2 – – – + + + Fig. 36.3. Regulation of pyruvate dehydroge- nase (PDH). A kinase associated with the PDH complex phosphorylates and inactivates the enzyme. 671CHAPTER 36 / INTEGRATION OF CARBOHYDRATES AND LIPID METABOLISM 6. ACETYL CoA CARBOXYLASE Acetyl CoA is converted to malonyl CoA, which provides the 2-carbon units for elongation of the growing fatty acyl chain on the fatty acid synthase complex. Acetyl CoA carboxylase, the enzyme that catalyzes the conversion of acetyl CoA to malonyl CoA, is controlled by three of the major mechanisms that regulate enzyme activity (Fig. 36.5). It is activated by citrate, which causes the enzyme to Pyruvate Glucose G–6–P Pyruvate Citrate Citrate OAA OAA Acetyl CoA Malate Malonyl CoA FA synthase Acetyl CoA ATP ADP + Pi NAD+ NADP+ NADPH NADP+ Palmitate G–6–P dehydrogenase CO2 NADH malic enzyme citrate lyase Fig. 36.4. Regulation of citrate lyase, malic enzyme, glucose 6-phosphate dehydrogenase, and fatty acid synthase. Citrate lyase, which provides acetyl CoA for fatty acid biosynthesis, the enzymes that provide NADPH (malic enzyme, glucose 6-phosphate dehydrogenase), as well as fatty acid synthase, are inducible (circled c ). – + + + Palmitoyl CoA Palmitate Malonyl CoA Acetyl CoA Citrate Glucose Insulin Low energy levels ADP ATP acetyl CoA carboxylase acetyl CoA carboxylase– P (inactive) AMP-activated protein kinase phosphatase Pi Fig. 36.5. Regulation of acetyl CoA carboxylase (AcC). AcC is regulated by activation and inhibition, by phosphorylation (mediated by the AMP-activated protein kinase) and dephos- phorylation (via an insulin-stimulated phosphatase), and by induction and repression. It is active in the fed state. 672 SECTION SIX / LIPID METABOLISM polymerize, and inhibited by long-chain fatty acyl CoA. A phosphatase stimulated by insulin activates the enzyme by dephosphorylation. The third means by which this enzyme is regulated is induction: the quantity of the enzyme increases in the fed state. Malonyl CoA, the product of the acetyl CoA carboxylase reaction, provides the carbons for the synthesis of palmitate on the fatty acid synthase complex. Malonyl CoA also inhibits carnitine:palmitoyltransferase I (CPTI, also known as carni- tine:acyltransferase I), the enzyme that prepares long-chain fatty acyl CoA for transport into mitochondria (Fig. 36.6). In the fed state, when acetyl CoA carboxy- lase is active and malonyl CoA levels are elevated, newly synthesized fatty acids are converted to triacylglycerols for storage, rather than being transported into mitochondria for oxidation and ketone body formation. 7. FATTY ACID SYNTHASE COMPLEX In a well-fed individual, the quantity of the fatty acid synthase complex is increased (see Fig. 36.4). The genes that produce this enzyme complex are induced by increases in the insulin/glucagon ratio. The amount of the complex increases slowly after a few days of a high-carbohydrate diet. Glucose 6-phosphate dehydrogenase, which generates NADPH in the pentose phosphate pathway, and malic enzyme, which produces NADPH, are also induced by the increase of insulin. The palmitate produced by the synthase complex is converted to palmityl CoA and elongated and desaturated to form other fatty acyl CoA molecules, which are converted to triacylglycerols. These triacylglycerols are packaged and secreted into the blood as VLDL. B. Mechanisms That Affect the Fate of Chylomicrons and VLDL The lipoprotein triacylglycerols in chylomicrons and VLDL are hydrolyzed to fatty acids and glycerol by lipoprotein lipase (LPL), an enzyme attached to endothelial cells of capillaries in muscle and adipose tissue. The enzyme found in muscle, par- ticularly heart muscle, has a low Km for these blood lipoproteins. Therefore, it acts even when these lipoproteins are present at very low concentrations in the blood. The fatty acids enter muscle cells and are oxidized for energy. The enzyme found in adipose tissue has a higher Km and is most active after a meal when blood lipoprotein levels are elevated. C. Mechanisms That Affect Triacylglycerol Storage in Adipose Tissue Insulin stimulates adipose cells to synthesize and secrete LPL, which hydrolyzes the chylomicron and VLDL triacylglycerols. The CII apoprotein, donated to chylomi- crons and VLDL by HDL, activates LPL (Fig. 36.7). Fatty acids released from chylomicrons and VLDL by LPL are stored as triacylglycerols in adipose cells. The glycerol released by LPL is not used by adi- pose cells because they lack glycerol kinase. Glycerol can be used by liver cells, however, because these cells do contain glycerol kinase. In the fed state, liver cells convert glycerol to the glycerol moiety of the triacylglycerols of VLDL, which is secreted from the liver to distribute the newly synthesized triglycerides to the tissues. Insulin causes the number of glucose transporters in adipose cell membranes to increase. Glucose enters these cells, and is oxidized, producing energy and provid- ing the glycerol 3-phosphate moiety for triacylglycerol synthesis (via the dihydroxyacetone phosphate intermediate of glycolysis). FA CoA FA CoA Palmitate Malonyl CoA Acetyl CoA FA synthase β–Oxidation CPTII Carnitine FA–carnitine FA CoACoASH –CPTI Fig. 36.6. Inhibition of transport of fatty acids (FA) into mitochondria by malonyl CoA. In the fed state, malonyl CoA (the substrate for fatty acid synthesis produced by acetyl CoA car- boxylase) is elevated. It inhibits CPTI, prevent- ing the transport of long-chain fatty acids into mitochondria. Therefore, substrate is not avail- able for �-oxidation and ketone body synthesis. Why does Ann Sulin have a hyper- triglyceridemia? Di Abietes has insulin-dependent diabetes mellitus (type 1), a dis- ease associated with a severe defi- ciency or absence of insulin production by the � cells of the pancreas. One of the effects of insulin is to stimulate production of LPL. Because of low insulin levels, Di Abietes tends to have low levels of this enzyme. Hydrolysis of the triacylglycerols in chylomi- crons and in VLDL is decreased, and hyper- triglyceridemia results. 673CHAPTER 36 / INTEGRATION OF CARBOHYDRATES AND LIPID METABOLISM Ann Sulin has type 2 diabetes mel- litus. She produces insulin, but her adipose tissue is resistant to its actions. Therefore, her adipose tissue does not produce as much LPL as a normal per- son, which is one of the reasons why VLDL and chylomicrons remain elevated in her blood. II. REGULATION OF CARBOHYDRATE AND LIPID METABOLISM DURING FASTING A. Mechanisms in Liver That Serve to Maintain Blood Glucose Levels During fasting, the insulin/glucagon ratio decreases. Liver glycogen is degraded to pro- duce blood glucose because enzymes of glycogen degradation are activated by cAMP- directed phosphorylation (Fig. 36.8). Glucagon stimulates adenylate cyclase to produce cAMP, which activates protein kinase A. Protein kinase A phosphorylates phosphory- lase kinase, which then phosphorylates and activates glycogen phosphorylase. Protein kinase A also phosphorylates but, in this case, inactivates glycogen synthase. Gluconeogenesis is stimulated because the synthesis of phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase is induced and because there is an increased availability of precursors. Fructose 1,6-bisphos- phatase is also activated because the levels of its inhibitor, fructose 2,6-bisphos- phate, are low (Fig. 36.9). During fasting, the activity of the corresponding enzymes of glycolysis is decreased. B. Mechanisms That Affect Lipolysis in Adipose Tissue During fasting, as blood insulin levels fall and glucagon levels rise, the level of cAMP rises in adipose cells. Consequently, protein kinase A is activated and causes phosphorylation of hormone-sensitive lipase (HSL). The phosphorylated form of this enzyme is active and cleaves fatty acids from triacylglycerols (Fig. 36.10). Other hormones (e.g., epinephrine, adrenocorticotropic hormone [ACTH], growth hormone) also activate this enzyme (see Chapter 43). Glyceroneogenesis and resyn- thesis of triglyceride by the adipocyte regulates the rate of release of fatty acids during fasting. C. Mechanisms That Affect Ketone Body Production by the Liver As fatty acids are released from adipose tissue during fasting, they travel in the blood complexed with albumin. These fatty acids are oxidized by various tissues, particularly muscle. In the liver, fatty acids are transported into mitochondria + + + FA Glycerol FACoA FA Blood Liver Chylomicrons Remnants VLDL IDL LDL Adipose cell LPL Glycerol–3–P DHAP Glucose Glucose Insulin TG CII Fed state L P L TG Fig. 36.7. Regulation of the storage of triacylglycerols (TG) in adipose tissue. Insulin stim- ulates the secretion of LPL from adipose cells and the transport of glucose into these cells. ApoCII activates LPL. FA � fatty acids. Twenty to thirty percent of patients with an insulinoma gain weight as part of their syndrome. Bea Selmass gained 8 lb in the 6 weeks before her surgery. Although she was primed by her high insulin levels both to store and to use fuel more effi- ciently, she would not have gained weight if
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