BIOL 238 Class Notes - Nutrition and Metabolism

Liver Pathology

Nutrition - Metabolism

Functions of the liver:
Manufacture -

blood proteins - albumen, clotting proteins

urea - nitrogenous waste from amino acid metabolism

bile - excretory for the bile pigments, emulsification of fats by bile salts

Storage -

glycogen - carbohydrate fuel

iron - as hemosiderin and ferritin

fat soluble vitamins A, D, E, K

Detoxification -

alcohol

drugs and medicines

environmental toxins

Protein metabolism - (See Figure 25.15)

transamination - removing the amine from one amino acid and using it to produce a different amino acid. The body can produce all but the essential amino acids; these must be included in the diet. (See Figure 25.3)

deamination - removal of the amine group in order to catabolize the remaining keto acid. The amine group enters the blood as urea which is excreted through the kidneys.

Glycemic Regulation - the management of blood glucose.

glycogenesis - the conversion of glucose into glycogen.

glycogenolysis - the breakdown of glycogen into glucose.

gluconeogenesis - the manufacture of glucose from non carbohydrate sources, mostly protein.

See Disorders below. See [Liver Pathology]

Structure of the liver - (See Figure 24.24) The liver is composed mostly of cells known as hepatocytes which perform the functions listed above. They have the ability to shift functions so their efforts can be directed at what is most needed. They can also divide to repair and replace tissue. Cirrhosis is a condition which can occur in the liver and other organs in which the cells are damaged as a result of toxins, pathogenic organisms, etc. Cirrhosis causes thickening and fibrosis and can progressively damage the liver to the point it can no longer recover by replacing its cells. Other functions also suffer as more hepatocytes become committed to detoxification.
The liver is organized into lobes and lobules. Each lobule is served by a branch from the portal vein, the hepatic artery and a bile duct. Blood from the artery and vein mixes in sinusoids passing through the lobule. Hepatocytes line the sinusoids and withdraw digestive endproducts, toxins, etc. from the blood. Into the blood the put urea, glucose, and other substances. Into the bile ductule they put bile to be taken to the gallbladder and common bile duct. Kupffer cells are found inside the sinusoids to phagocytize debris, rbc, and pathogens.

The phases of glycemic regulation -

Absorptive Phase - in this phase digestive endproducts are being absorbed from the gut and being sent to storage. The processes occurring during this phase are:

1) glycogenesis - glucose from the blood plasma is moved into the liver for storage as glycogen. The hormone which governs this is insulin.
2) protein manufacture - amino acids absorbed from the blood are transaminated and made into proteins.
3) fats move into the fat reserves of the body. Insulin enhances this as well.

Post-absorptive Phase - in this phase glucose is moved back into the blood to supply what is used in metabolism.

1) glycogenolysis - the first source of glucose is the breakdown of glycogen. The primary hormone for this is glucagon. Epinephrine also causes release of glucose into the blood when the sympathetic nervous system is activated.
2) lipolysis - fat is broken down into glycerol and fatty acids. Glycerol is used to make glucose or in glycolysis. Fatty acids can be catabolized by many cells, especially aerobic muscle fibers. This is said to be "glucose sparing" because it leaves glucose available for those cells, e.g. neurons, which rely on glucose exclusively. Glucagon and epinephrine also trigger lipolysis. Lipolysis begins when glycogen reserves fall to about 1/3 of maximum.
3) gluconeogenesis - Amino acids are made into glucose under two conditions: a) when they are in abundance as in a high protein, low carbohydrate diet, an action mediated by glucagon; and b) when other fuel reserves are low or when severe stress causes release of cortisol. Cortisol causes proteins from muscles and connective tissue to be broken down into amino acids to make glucose. Fats are not made into glucose under normal circumstances (except for the glycerol, as above), but in high fat diets or when carbohydrate fuel is unavailable the body shifts to utilizing fat to make glucose.

The Hormones: [Also see Endocrine Notes - Diabetes Mellitus]
insulin - (See Figure 25.18) produced by the beta cells of the Islets of Langerhans, these cells are part of the endocrine portion of the pancreas which consists of islands surrounded by pancreatic exocrine cells. Insulin lowers blood glucose by triggering glycogenesis and its uptake by other cells for metabolism. The stimulus for insulin release is rising blood glucose during the absorptive phase which acts directly on the beta cells. In Type I (insulin dependent) diabetes mellitus the pancreas does not secrete enough insulin and insulin injections or oral administration are used to compensate. The amount of insulin taken must match the amount of carbohydrates consumed.
glucagon - (See Figure 25.20) Is produced by the alpha cells of the Islets of Langerhans. Glucagon release is triggered by lowering blood glucose levels which occurs during the post-absorptive phase when glucose is withdrawn from the blood for metabolism. Glucagon causes glycogenolysis and lipolysis to yield more glucose and fatty acids for fuel. As blood glucose rises it will stimulate the release of insulin by the beta cells. This is a confusing yet important response. Insulin is necessary for uptake of the glucose for cellular metabolism. And by this mechanisms of two antagonistic hormones glucose levels can be precisely controlled under normal circumstances. We will more thoroughly discuss hyper- and hypoglycemia and diabetes mellitus at a later time.
epinephrine - (See Figure 25.21) Epinephrine is released by the adrenal medulla into the blood and directly from sympathetic stimulation when the sympathetic nervous system is activated. It causes glycogenolysis and lipolysis which releases fuel for "fight or flight", exercise, and other stressors. NOTE: glycogenolysis in muscles releases glucose for muscle contraction, and does not directly contribute to blood glucose. However this effect is also "glucose sparing" in that plasma glucose is then available for other uses.
cortisol (cortisone) - Cortisone is released from the adrenal cortex during periods of extreme physical stress. Called a glucocorticoid, this hormone makes fuel available for metabolism, repair and replacement of tissue. This fuel comes mostly from the breakdown of proteins in muscle and connective tissue. Cortisol also has anti-immune and anti-inflammatory effects which are utilized clinically when injury occurs and to suppress the immune response. Administered over a period of time this also results in tissue damage from the hormone's catabolic effects.

Cellular metabolism: C₆H₁₂O₆ + O₂ ---> CO₂ + H₂O
These concepts should be a review of material previously studied, and our discussion is intended only to refresh your memory and to relate the metabolic pathways to the overall discussion of nutrition.
Glycolysis - (See Figure 25.7)All cells process glucose initially by glycolysis. Those cells capable of aerobic metabolism will then feed the product of glycolysis, pyruvic acid, into the aerobic pathway. Glycolysis by itself is anaerobic, i.e. it doesn't required oxygen. So it represents a prime source of energy for cells specializing in anaerobic metabolism, namely the white muscle fibers which function in speed and strength activities. In glycolysis each molecule of glucose is broken down into two molecules of pyruvic acid. An intermediate of importance is G-3-P, glyceraldehyde 3 phosphate. G-3-P is important as the input to glycolysis of glycerol from lipolysis. G-3-P can be reconverted to glucose or go on to pyruvic acid. The manufacture of pyruvic acid yields a net of 2 ATP molecules. It also yields reduced electron acceptors which carry the high energy electrons (designated here as H⁺/e^-) to the electron transport system in the mitochondrion. There the energy from these electrons is used to make ATP. But that requires oxygen and so is not part of glycolysis. Glycolysis takes place in the cells cytoplasm.
Fermentation - when oxygen is unavailable the pyruvic acid is converted to lactic acid. The enables glycolysis to be extended, since buildup of the product of a reaction will eventually slow that reaction down. But lactic acid also accumulates eventually causing muscle fatigue as it slows glycolysis and ATP is used up. Lactic acid is also responsible for the burning sensation that accompanies intense muscle activity. It is not the cause of the muscle's soreness afterward. Most lactic and pyruvic acid is removed from anaerobic muscle fibers and carried to the liver to be metabolized.
Krebs Cycle - (See Figure 25.8) When oxygen is available the pyruvic acid is taken into the mitochondrion for processing aerobically. The reduced electron acceptors also are carried into the mitochondrion, a process which in some cells requires ATP. The pyruvic acid is split into a 2 carbon group called an acetyl group, and the third carbon together with 2 oxygen atoms becomes CO₂. The acetyl group is grabbed by a molecule of coenzyme A and handed off to a molecule of oxaloacetic acid (called the pickup molecule in your text). Since oxaloacetic is 4 carbons, when added to the 2 carbon acetyl group it produces a 6 carbon molecule called citric acid. Another name for this cycle is the Citric Acid Cycle in honor of its first product. The coenzyme A can be used over and over again to hand off acetyl groups to oxaloacetic acid. As the cycle proceeds, the bonds of the acetyl group are broken apart and the energy and H⁺/e^-captured as reduced electron acceptors, or made directly into ATP. Called substrate phosphorylation by Marieb, only 2 more ATP molecules are produced in this way from each glucose. The carbon and oxygen atoms are made into CO2 and each step yields a new molecule until the original oxaloacetic acid is produced and ready to accept another acetyl group.

Electron Transport System - (See Figures 25.9, 25.10) This system is within the mitochondrion and consists of a series of electron acceptors molecules in what some call a cascade. Many of these molecules are ion-containing cytochromes (cell colors). As each molecule first picks up and then gives off electrons, it becomes reduced and then oxidized and the energy is given up. In an indirect mechanism called a proton pump the energy is used to pump protons or hydrogen ions across a membrane and as these ions move back along the gradient produced their energy is used to make ATP. At the top of the cascade the electrons are still high energy electrons but at the bottom or end of the process their energy has been released. These "low energy" electrons are recombined with the hydrogen ions together with oxygen from respiration to make the other waste product, water. Most of the ATP, 34 of the 36 or 38 produced, is produced by the electron transport system. For an energy summary see Figure 25.11. Green text indicates more than you need to know for this class.

Electron acceptors: Electron acceptors latch on to the high energy electrons and their accompanying hydrogen ions (H+/e-) and transport them to the electron transport system. They are derived and replaced from vitamins. See the [Vitamin List] in your objectives for vitamins related to metabolism and other processes.
NAD - nicotinamide adenine dinucleotide, derived from niacin. As NAD picks up the H+/e- is becomes NADH. Each electron from NADH yields 3 ATP.
FAD - flavin adenine dinucleotide, derived from the vitamin riboflavin. Usually designated FADH it picks up a H+/e- to become FADH2. Because it enters at a lower spot on the chain each H+/e- from this acceptor only yields 2 ATP.

Metabolism of Fats:
Fats are lipolyzed into glycerol and fatty acids. The glycerol is converted to G-3-P and can be reconverted to glucose, or continue in glycolysis. The fatty acids are long chain hydrocarbons with a carboxyl group at one end. They are cleaved into acetyl groups in the process known as beta oxidation. The acetyl groups are then processed aerobically. Not all cells can perform beta oxidation, but your red muscle fibers are responsible for most of it normally. The process also yields reduced electron acceptors. The carboxyl groups are known as "ketone bodies" and are slower to be metabolized. When they accumulate, as they do in a Type I diabetic with insufficient insulin, they can cause acidosis. Also called ketoacidosis, it is a life-threatening complication for insulin-dependent (Type I) diabetes. Fats yield between 8 and 9 kcal/gram.

Protein metabolism - as noted earlier, amino acids are first deaminized to produce a keto acid. The keto acids can be plugged into the aerobic pathway at many points depending on their particular structure. They are therefore readily metabolized and do not accumulate and do not, despite their name, contribute to ketoacidosis in diabetics.

Disorders: See [Liver Pathology]
cirrhosis

hepatitis

Nutrition - Metabolism
Functions of the liver: Manufacture - blood proteins - albumen, clotting proteins urea - nitrogenous waste from amino acid metabolism bile - excretory for the bile pigments, emulsification of fats by bile salts Storage - glycogen - carbohydrate fuel iron - as hemosiderin and ferritin fat soluble vitamins A, D, E, K Detoxification - alcohol drugs and medicines environmental toxins Protein metabolism - (See Figure 25.15) transamination - removing the amine from one amino acid and using it to produce a different amino acid. The body can produce all but the essential amino acids; these must be included in the diet. (See Figure 25.3) deamination - removal of the amine group in order to catabolize the remaining keto acid. The amine group enters the blood as urea which is excreted through the kidneys. Glycemic Regulation - the management of blood glucose. glycogenesis - the conversion of glucose into glycogen. glycogenolysis - the breakdown of glycogen into glucose. gluconeogenesis - the manufacture of glucose from non carbohydrate sources, mostly protein. See Disorders below. See [Liver Pathology]
Structure of the liver - (See Figure 24.24) The liver is composed mostly of cells known as hepatocytes which perform the functions listed above. They have the ability to shift functions so their efforts can be directed at what is most needed. They can also divide to repair and replace tissue. Cirrhosis is a condition which can occur in the liver and other organs in which the cells are damaged as a result of toxins, pathogenic organisms, etc. Cirrhosis causes thickening and fibrosis and can progressively damage the liver to the point it can no longer recover by replacing its cells. Other functions also suffer as more hepatocytes become committed to detoxification. The liver is organized into lobes and lobules. Each lobule is served by a branch from the portal vein, the hepatic artery and a bile duct. Blood from the artery and vein mixes in sinusoids passing through the lobule. Hepatocytes line the sinusoids and withdraw digestive endproducts, toxins, etc. from the blood. Into the blood the put urea, glucose, and other substances. Into the bile ductule they put bile to be taken to the gallbladder and common bile duct. Kupffer cells are found inside the sinusoids to phagocytize debris, rbc, and pathogens.
	The phases of glycemic regulation - Absorptive Phase - in this phase digestive endproducts are being absorbed from the gut and being sent to storage. The processes occurring during this phase are: 1) glycogenesis - glucose from the blood plasma is moved into the liver for storage as glycogen. The hormone which governs this is insulin. 2) protein manufacture - amino acids absorbed from the blood are transaminated and made into proteins. 3) fats move into the fat reserves of the body. Insulin enhances this as well. Post-absorptive Phase - in this phase glucose is moved back into the blood to supply what is used in metabolism. 1) glycogenolysis - the first source of glucose is the breakdown of glycogen. The primary hormone for this is glucagon. Epinephrine also causes release of glucose into the blood when the sympathetic nervous system is activated. 2) lipolysis - fat is broken down into glycerol and fatty acids. Glycerol is used to make glucose or in glycolysis. Fatty acids can be catabolized by many cells, especially aerobic muscle fibers. This is said to be "glucose sparing" because it leaves glucose available for those cells, e.g. neurons, which rely on glucose exclusively. Glucagon and epinephrine also trigger lipolysis. Lipolysis begins when glycogen reserves fall to about 1/3 of maximum. 3) gluconeogenesis - Amino acids are made into glucose under two conditions: a) when they are in abundance as in a high protein, low carbohydrate diet, an action mediated by glucagon; and b) when other fuel reserves are low or when severe stress causes release of cortisol. Cortisol causes proteins from muscles and connective tissue to be broken down into amino acids to make glucose. Fats are not made into glucose under normal circumstances (except for the glycerol, as above), but in high fat diets or when carbohydrate fuel is unavailable the body shifts to utilizing fat to make glucose.
The Hormones: [Also see Endocrine Notes - Diabetes Mellitus] insulin - (See Figure 25.18) produced by the beta cells of the Islets of Langerhans, these cells are part of the endocrine portion of the pancreas which consists of islands surrounded by pancreatic exocrine cells. Insulin lowers blood glucose by triggering glycogenesis and its uptake by other cells for metabolism. The stimulus for insulin release is rising blood glucose during the absorptive phase which acts directly on the beta cells. In Type I (insulin dependent) diabetes mellitus the pancreas does not secrete enough insulin and insulin injections or oral administration are used to compensate. The amount of insulin taken must match the amount of carbohydrates consumed. glucagon - (See Figure 25.20) Is produced by the alpha cells of the Islets of Langerhans. Glucagon release is triggered by lowering blood glucose levels which occurs during the post-absorptive phase when glucose is withdrawn from the blood for metabolism. Glucagon causes glycogenolysis and lipolysis to yield more glucose and fatty acids for fuel. As blood glucose rises it will stimulate the release of insulin by the beta cells. This is a confusing yet important response. Insulin is necessary for uptake of the glucose for cellular metabolism. And by this mechanisms of two antagonistic hormones glucose levels can be precisely controlled under normal circumstances. We will more thoroughly discuss hyper- and hypoglycemia and diabetes mellitus at a later time. epinephrine - (See Figure 25.21) Epinephrine is released by the adrenal medulla into the blood and directly from sympathetic stimulation when the sympathetic nervous system is activated. It causes glycogenolysis and lipolysis which releases fuel for "fight or flight", exercise, and other stressors. NOTE: glycogenolysis in muscles releases glucose for muscle contraction, and does not directly contribute to blood glucose. However this effect is also "glucose sparing" in that plasma glucose is then available for other uses. cortisol (cortisone) - Cortisone is released from the adrenal cortex during periods of extreme physical stress. Called a glucocorticoid, this hormone makes fuel available for metabolism, repair and replacement of tissue. This fuel comes mostly from the breakdown of proteins in muscle and connective tissue. Cortisol also has anti-immune and anti-inflammatory effects which are utilized clinically when injury occurs and to suppress the immune response. Administered over a period of time this also results in tissue damage from the hormone's catabolic effects.
	Cellular metabolism: C₆H₁₂O₆ + O₂ ---> CO₂ + H₂O These concepts should be a review of material previously studied, and our discussion is intended only to refresh your memory and to relate the metabolic pathways to the overall discussion of nutrition. Glycolysis - (See Figure 25.7)All cells process glucose initially by glycolysis. Those cells capable of aerobic metabolism will then feed the product of glycolysis, pyruvic acid, into the aerobic pathway. Glycolysis by itself is anaerobic, i.e. it doesn't required oxygen. So it represents a prime source of energy for cells specializing in anaerobic metabolism, namely the white muscle fibers which function in speed and strength activities. In glycolysis each molecule of glucose is broken down into two molecules of pyruvic acid. An intermediate of importance is G-3-P, glyceraldehyde 3 phosphate. G-3-P is important as the input to glycolysis of glycerol from lipolysis. G-3-P can be reconverted to glucose or go on to pyruvic acid. The manufacture of pyruvic acid yields a net of 2 ATP molecules. It also yields reduced electron acceptors which carry the high energy electrons (designated here as H⁺/e^-) to the electron transport system in the mitochondrion. There the energy from these electrons is used to make ATP. But that requires oxygen and so is not part of glycolysis. Glycolysis takes place in the cells cytoplasm. Fermentation - when oxygen is unavailable the pyruvic acid is converted to lactic acid. The enables glycolysis to be extended, since buildup of the product of a reaction will eventually slow that reaction down. But lactic acid also accumulates eventually causing muscle fatigue as it slows glycolysis and ATP is used up. Lactic acid is also responsible for the burning sensation that accompanies intense muscle activity. It is not the cause of the muscle's soreness afterward. Most lactic and pyruvic acid is removed from anaerobic muscle fibers and carried to the liver to be metabolized. Krebs Cycle - (See Figure 25.8) When oxygen is available the pyruvic acid is taken into the mitochondrion for processing aerobically. The reduced electron acceptors also are carried into the mitochondrion, a process which in some cells requires ATP. The pyruvic acid is split into a 2 carbon group called an acetyl group, and the third carbon together with 2 oxygen atoms becomes CO₂. The acetyl group is grabbed by a molecule of coenzyme A and handed off to a molecule of oxaloacetic acid (called the pickup molecule in your text). Since oxaloacetic is 4 carbons, when added to the 2 carbon acetyl group it produces a 6 carbon molecule called citric acid. Another name for this cycle is the Citric Acid Cycle in honor of its first product. The coenzyme A can be used over and over again to hand off acetyl groups to oxaloacetic acid. As the cycle proceeds, the bonds of the acetyl group are broken apart and the energy and H⁺/e^-captured as reduced electron acceptors, or made directly into ATP. Called substrate phosphorylation by Marieb, only 2 more ATP molecules are produced in this way from each glucose. The carbon and oxygen atoms are made into CO2 and each step yields a new molecule until the original oxaloacetic acid is produced and ready to accept another acetyl group.
Electron Transport System - (See Figures 25.9, 25.10) This system is within the mitochondrion and consists of a series of electron acceptors molecules in what some call a cascade. Many of these molecules are ion-containing cytochromes (cell colors). As each molecule first picks up and then gives off electrons, it becomes reduced and then oxidized and the energy is given up. In an indirect mechanism called a proton pump the energy is used to pump protons or hydrogen ions across a membrane and as these ions move back along the gradient produced their energy is used to make ATP. At the top of the cascade the electrons are still high energy electrons but at the bottom or end of the process their energy has been released. These "low energy" electrons are recombined with the hydrogen ions together with oxygen from respiration to make the other waste product, water. Most of the ATP, 34 of the 36 or 38 produced, is produced by the electron transport system. For an energy summary see Figure 25.11. Green text indicates more than you need to know for this class.
Electron acceptors: Electron acceptors latch on to the high energy electrons and their accompanying hydrogen ions (H+/e-) and transport them to the electron transport system. They are derived and replaced from vitamins. See the [Vitamin List] in your objectives for vitamins related to metabolism and other processes. NAD - nicotinamide adenine dinucleotide, derived from niacin. As NAD picks up the H+/e- is becomes NADH. Each electron from NADH yields 3 ATP. FAD - flavin adenine dinucleotide, derived from the vitamin riboflavin. Usually designated FADH it picks up a H+/e- to become FADH2. Because it enters at a lower spot on the chain each H+/e- from this acceptor only yields 2 ATP.
Metabolism of Fats: Fats are lipolyzed into glycerol and fatty acids. The glycerol is converted to G-3-P and can be reconverted to glucose, or continue in glycolysis. The fatty acids are long chain hydrocarbons with a carboxyl group at one end. They are cleaved into acetyl groups in the process known as beta oxidation. The acetyl groups are then processed aerobically. Not all cells can perform beta oxidation, but your red muscle fibers are responsible for most of it normally. The process also yields reduced electron acceptors. The carboxyl groups are known as "ketone bodies" and are slower to be metabolized. When they accumulate, as they do in a Type I diabetic with insufficient insulin, they can cause acidosis. Also called ketoacidosis, it is a life-threatening complication for insulin-dependent (Type I) diabetes. Fats yield between 8 and 9 kcal/gram.
Protein metabolism - as noted earlier, amino acids are first deaminized to produce a keto acid. The keto acids can be plugged into the aerobic pathway at many points depending on their particular structure. They are therefore readily metabolized and do not accumulate and do not, despite their name, contribute to ketoacidosis in diabetics.
Disorders: See [Liver Pathology] cirrhosis hepatitis