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8 - Summary of Macronutrient Metabolism
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This lesson summarises the overall metabolism of carbohydrates, lipids and proteins. It draws together the information containing in lessons 4 to 7. It reviews the interrelationship between carbohydrate, lipid and protein metabolism. It also reviews the common catabolic and biosynthetic processes that occur in both the fed and fasted states.
Relationship Between Carbohydrate, Lipid and Protein Metabolism
Carbohydrates, lipids and proteins are all capable of providing the body with the energy that it needs on a short-term basis. This is of course assuming that sufficient quantities of these macronutrients are being eaten. When consumed in excess, all of these macronutrients are also capable of being stored in the body as fat. Furthermore, the body has the ability to produce one macronutrient from another if needed. For example, amino acids can be synthesised from carbohydrates or fats. Conversely, most amino acids can be used to synthesise carbohydrates or fat.
There are certain limitations to these processes. The glycerol component of fat can be converted to carbohydrate, however the fatty acid component cannot. This is because the reaction that uses pyruvate dehydrogenase is not reversible. Acetyl CoA (produced from the breakdown of fatty acids with an even number of carbons) is therefore unable to be converted into pyruvate (for the new synthesis of glucose). Glucose is however, the precursor for the synthesis of both the glycerol and fatty acid components of triglycerides.
This close relationship between the metabolism of carbohydrates, lipids and proteins is vital. The interconversion of the macronutrients is geared towards allowing the body to be able to maintain its supply of energy even when a particular macronutrient is insufficiently supplied.
The citric acid cycle is very important as it is central to macronutrient metabolism. It breaks down carbohydrates, lipids and proteins, as well as producing many of the precursors required for biosynthesis. It supplies the intermediate products that provide the links between lipids, carbohydrate and protein metabolism.
How 'fattening' are carbohydrates?
Animals have traditionally been fed a largely carbohydrate-based diet in order to fatten them up. This was a practical demonstration of just how easily carbohydrates seemed to able to be converted into fat stores. The conversion of ingested glucose to fat stores in humans may not actually be quite as efficient as once thought. The conversion of dietary carbohydrates into fat stores is thought to occur via the suppression of lipolysis (breakdown of fats) rather than by a more direct production of fat stores from glucose. Unfortunately, this still means that the long-term consumption of carbohydrates (or any other macronutrient) in excess of a person's caloric needs can lead to weight gain.
Metabolic Processes Requiring Energy
Available cellular energy must be shared amongst the different processes going on in a cell. There is only a finite amount of energy in the cell available at any time. Energy is generated from the catabolism of macronutrients (the breakdown of carbohydrates, fats and proteins). It is usually used in the form of ATP, NADH, NADP or FADH2. This sharing of energy means that if the cell needs to urgently synthesise a particular component, another energy-producing component must broken down in order to provide the energy needed. It also means that a cell cannot carry out multiple energy-requiring processes all at the same time. For example, if the liver is synthesising glucose, it cannot synthesise lipids and proteins at the same time.
Fed and Fasted State
Most people tend to have a number of meals per day which are followed by periods where no food is consumed (although some people do like to 'graze' or nibble!). During a meal, the caloric intake (the intake of energy from food) is much greater than the body's immediate energy needs. This short period of excess energy intake allows people to go without food until the next meal.
The balance of glucose levels in the body must be maintained at a constant level both during meals and in the gaps between meals (the fasted state). It is important that tissues are adequately supplied with their preferred source of energy (glucose) throughout the course of the day. The mechanisms that the body uses to maintain a constant supply of blood glucose vary depending on the length of time in a fasted state.
When energy intake (the energy provided by food and beverages) exceeds energy expenditure, the excess energy is stored as glycogen or fat. Energy expenditure includes the energy required to breakdown, absorb, metabolise and store macronutrients, as well as the energy required for body functions such as breathing, the beating of the heart, temperature regulation and physical activity. Glycogen and fat stores can be used to provide the body with energy when required.
• Fed State - The body is considered to be in a fed state up to 3 hours after a meal has been eaten (obviously this depends on what was eaten and how much was eaten).
• Early Fasting State (post-absorptive) - From around 3 hours after a meal until 12 to 18 hours following a meal is considered to be an early fasting state (or a post-absorptive state).
• Fasting State - This lasts from around 18 hours after a meal, up to 2 days (without any food being consumed). The mechanisms used to maintain blood glucose levels change when a fasted state goes for longer than around 18 hours.
• Starvation or Long-Term Fast - The body adapts to the state of fasting. This adaptation can last as long as several weeks.
Macronutrient Metabolism in the Fed State
Both mechanical (chewing) and chemical (saliva) breakdown of food occurs in the mouth. The enzymes lipase and amylase are secreted in the mouth, although they contribute minimally to the overall digestion of fats and carbohydrates. Food is transported to the stomach via the esophagus, where it is mixed with stomach acid, pepsin (which breaks down proteins into large polypeptides) and gastric lipase. Food then moves into the small intestine where the majority of digestion and absorption takes place. The presence of the partially digested food in the small intestine triggers the release of hormones which signal the pancreas to secrete digestive enzymes and the gallbladder to release bile. Protein is broken down into small polypeptides and amino acids, carbohydrates are broken down into their monosaccharide constituents (and a small number of disaccharides), and fats are broken down into free fatty acids, monoglycerides and cholesterol. Figure to Figure 8.2 as the individual metabolism of glucose, amino acids and fats are discussed below.
Monosaccharides are transported as plasma glucose (by GLUT transporters) to the liver. Increased concentrations of glucose in the portal vein trigger the release of insulin from the pancreas. Insulin increases the uptake of glucose into muscle and adipose tissue by causing the GLUT4 transporters to be moved from intracellular storage vesicles to the surface of the cell membrane (ready to transport glucose). The liver takes up around 50% of the glucose via GLUT2 transporters (which are non-insulin dependent). The glucose (and other dietary monosaccharides) taken up in the liver are immediately converted to glucose 6-phosphate (the first step of glycolysis). This immediate conversion encourages glucose entry into the liver, when blood glucose levels are elevated.
Insulin enhances the activity of the enzyme (which in the liver is glucokinase and in the muscle, hexokinase) which converts glucose to glucose 6-phosphate. Glycolysis (the breakdown of glucose) produces pyruvate. When there is sufficient oxygen available, pyruvate will be converted to acetyl CoA by pyruvate dehydrogenase. Insulin also stimulates the activity of pyruvate dehydrogenase. Insulin therefore increases glycolysis and the subsequent production of acetyl CoA. Acetyl CoA enters the citric acid cycle and produces ATP (ATP is primarily generated through electron transport and oxidative phosphorylation).
Red blood cells and the central nervous system use available glucose in the bloodstream as an immediate energy source. Glucose in the central nervous system is catabolised by glycolysis and then the citric acid cycle. Red blood cells do not have mitochondria, so they anaerobically convert glucose into lactate (via glycolysis), to create the small amount of energy that the cell requires.
Glucose that is not immediately needed by the body can be stored as glycogen. The liver is a major site for glycogen synthesis and storage, but it is also stored in skeletal muscle, and to a lesser extent, adipose tissue. Glycogen ensures that the body has a reserve of instant energy when it is required. Insulin enhances the activity of glycogen synthase, the enzyme that incorporates glucose into glycogen as UDP-glucose. The increased activity of glycogen synthase in the liver and muscles, is important for maximising the storage of glucose as glycogen in the fed state.
Once carbohydrate intake exceeds the body's ability to break it down through glycolysis or store it as glycogen, cells can metabolise it in a number of ways (e.g., the pentose phosphate pathway can use glucose to produce nucleotides). The conversion of excess glucose into fatty acids appears to only occur if energy intake exceeds energy expenditure. Insulin increases the activity of fatty acid and triglyceride synthesis enzymes (e.g., acetyl CoA carboxylase in the liver, lipoprotein lipase in adipose tissue and fatty acid synthetase). Fatty acids can then be stored in adipose tissue ready to provide energy during fasting states.
While some glycogen can be synthesised directly from glucose, research indicates the most glycogen synthesis may actually occur via a slightly more convoluted route! Glycogen can be synthesised from precursors such as pyruvate, alanine and lactate. These substances are returned to the liver from the periphery.
Most dietary fat is transported by chylomicrons (a lipoprotein transporter). Once in the intestinal mucosal cells, free fatty acids and monoglycerides (broken down in the digestive process) are re-formed into triglycerides and packaged into chylomicrons for transport. Chylomicrons pass into the lymphatic system, are transported to the thoracic duct, and are then emptied into the bloodstream. The chylomicrons then travel through the blood to adipose tissue. The enzyme lipoprotein lipase is present on the membrane of capillary cells near the adipocytes (fat cells). It binds the chylomicrons and cleaves the triglycerides into free fatty acids and monoglycerides. The free fatty acids and monoglycerides enter the adipocytes and are reformed into triglycerides for safe storage in adipose tissue. Insulin increases lipoprotein lipase activity in adipose tissue after feeding (lipoprotein lipase activity is low during fasted states).
The liver receives fat from chylomicron remnants, circulating fatty acids, lipoproteins and its own endogenous synthesis. In the fed state, the liver forms VLDLs with the fats and transports them to adipocytes for storage.
Under most circumstances, fatty acids are the major source of energy for the liver. They are oxidised through the citric acid cycle to product ATP. When there is an inadequate carbohydrate intake (even if caloric intake is adequate) or when glucose cannot be effectively used (e.g., diabetes mellitus), the breakdown of fatty acids (b-oxidation) is accelerated. Not all of the acetyl CoA formed is able to be oxidised through the citric acid cycle. The overflow of acetyl CoA is converted into keton bodies (acetoacetate and b-hydroxybutyrate). Ketone bodies are transported from the liver to peripheral tissues where they are converted back to acetyl CoA and oxidised through the citric acid cycle to generate ATP.
Polypeptides are broken down into amino acids and small peptides and are absorbed along the entire length of the small intestine. The majority of amino acids are thought to be transported across the brush border by sodium-dependent transporters. The same transporters are thought to carry the amino acids from the intestinal cells into the circulation, where they are taken to the liver for metabolism.
Many amino acids remain in the intestinal cells and are used by them for energy The intestinal cells also use amino acids to produce other amino acids, structural proteins for new intestinal cells, nucleotides, apoproteins necessary for lipoprotein formation, new digestive enzymes, hormones and nitrogen-containing compounds. The intestines may actually use up to 90% of glutamate absorbed from dietary protein.
The liver takes up most of the amino acids after the ingestion of a meal (around 50 to 65%). While amino acids are primarily used to synthesise new proteins in the body, excess amino acids can be catabolised to produce energy. The liver is thought to be able to monitor the absorbed amino acids and to make adjustments to their metabolism (breakdown or synthesis) according to the body's needs. Immediately after a meal is eaten, it is thought that around 20% of amino acids are used to synthesise proteins and nitrogen-containing compounds (e.g., neurotransmitters, carnitine, creatine, choline, nucleotides). Amino acids that are catabolised in the liver are mostly transaminated and then degraded to acetyl CoA or other citric acid cycle intermediates. These substances can then be oxidised by generate ATP, or converted to glucose or fat.
All amino acids can be used to produce energy. The carbon skeleton of glucogenic amino acids can be used to synthesise glucose when there is an inadequate calorie intake or insufficient carbohydrate intake. Glucose is formed via gluconeogenesis, and this new glucose can be transported to muscle for the muscle tissue to use. Ketogenic amino acids (which generate acetyl CoA or acetoacetate) can be catabolised to form ketone bodies when carbohydrate intake is insufficient. Fatty acids can be synthesised from the carbon skeletons of amino acids. The newly synthesised fatty acids can be used by the muscles for energy, or they can be transported to adipose tissue and stored. Fatty acid synthesis from amino acids occurs when there is an excess energy and protein intake, combined with an adequate carbohydrate intake.
Macronutrient Metabolism in the Early Fasting State
At the state of the early fasting state (around 3 hours after a meal) the body can no longer derive its energy directly from ingested glucose or other macronutrients. It needs to start relying on other sources of fuel. During the early fasting state the major source of glucose for the bloodstream is from glycogenolysis (the breakdown of glycogen) in the liver (glycogenolysis occurs in muscles but the glucose produced is only able to be used as fuel by muscle cells). The glucose resides in glycogen are systematically cleaved from the ends of branches in accordance with the body's energy demands.
Glycogenolysis is regulated by the pancreatic hormone glucagon (and also epinephrine). Glucagon is secreted by pancreatic alpha cells and is released in response to lowered blood glucose levels. It binds to receptors on liver cells and stimulates the increased release of glucose into the blood. Glucagon (acting through cAMP) activates the enzyme protein kinase, which is responsible for the phosphorylation of many target enzymes. Protein kinase phosphorylates fructose bisphosphatase 2 (activating it) and phosphofructokinase 2 (inactivating it). This results in reduced concentration of fructose 2,6 bisphosphate; increasing gluconeogenesis and decreasing glycolysis. When glycogenolysis is occurring, the synthesis of glycogen and triglycerides in the liver is diminished. The new synthesis of glucose (gluconeogenesis) in the liver begins to help in maintaining blood glucose levels. Pyruvate, lactate, oxaloacetate, malate and glucogenic amino acids are all compounds that glucose can be synthesised from.
The brain and other central nervous system tissues consume a lot of glucose for energy. They also do not generate any gluconeogenic precursors. This means that glucose utilisation outstrips the liver's ability to produce glucose, and glycogen stores are rapidly diminished. During an overnight fast, nearly all liver glycogen and most muscle glycogen is used up.
Macronutrient Metabolism in the Fasted State
The fasted state is considered to be from about 18 hours after a meal to around 48 hours (with no food intake). Once glycogen has been depleted (this will occur within 24 hours), gluconeogenesis in the liver becomes the primary source of energy for the body. Muscle protein is broken down to provide the amino acids the liver needs as substrates for gluconeogenesis. The hormones epinephrine, thyroxine and glucagon stimulate the release of muscle protein. Amino acids provide the primary source of substrates, however glycerol (from the breakdown of triglycerides) and lactate (from the anaerobic metabolism of glucose) are also used by the liver for gluconeogenesis. Only the amino acids leucine and lysine cannot be used for gluconeogenesis, as they are totally ketogenic. They are used to generate ketone bodies which can be used for energy by the muscles, brain and heart. The amino acid alanine is the most common substrate for gluconeogenesis, as when its nitrogen is removed, it becomes pyruvate.
Glycogen is not actually ever fully depleted. A small amount remains even during long-term starvation. The body needs to retain a small amount of glycogen as a primer for the re-synthesis of new glycogen stores.
The Flow of Substrates
Macronutrient Metabolism in Starvation
If fasting becomes long-term or starvation occurs, the body shifts its metabolism to try and spare body protein. Protein is vital for the production of life-sustaining compounds such as antibodies, enzymes and haemoglobin. The body therefore shifts from predominantly relying on gluconeogenesis to lipolysis (the breakdown of fats) to provide energy. As fasting becomes prolonged, liver gluconeogenesis decreases from producing around 90% of the glucose in the body, to less than 50%. The kidneys start to supply the remainder of the glucose in the body through gluconeogenesis.
The amount of fatty acids in the bloodstream increases and fatty acids are used as the primary fuel for the heart, liver and muscles. Low insulin levels and raised glucagon, epinephrine, growth hormone and cortisol levels stimulate the release of fatty acids. The brain is unable to use the fatty acids (as they cannot cross the blood brain barrier), but it can use glycerol as a gluconeogenic precursor. The brain and muscles also continue to use ketone bodies for energy. Oxaloacetate becomes depleted as more and more citric acid cycle intermediates are used up for gluconeogenesis. The increased breakdown of fats and the depleted pool of oxaloacetate results in an accumulation of acetyl CoA. Under normal conditions, the liver would convert acetyl CoA into ketone bodies. They would be transported in the blood from the liver to peripheral tissues, where they would be converted back to acetyl CoA and used for energy (in the citric acid cycle). During starvation (and untreated diabetes mellitus) ketone bodies can accumulate in the blood and reach high concentrations. This results in ketosis, which is potentially dangerous due to the disturbance it causes to the body's acid-base balance.
The amount of time a person can survive using these mechanisms depends on their quantity of fat stores. A person with 'normal' weight and body fat stores is able to generate enough energy to sustain their body for around 3 months. While a very obese adult has enough energy stored to supply the body for around 12 months, physiological damage or death will occur from the damage caused by ketosis. Once fat stores have been depleted, the body once again turns to protein to supply the necessary fuel for ATP production. This causes a loss of muscle and liver function, which ultimately leads to death.
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