Metabolism Flashcards
(31 cards)
Functions of the Liver in Metabolism
After absorption from the gut, sugars, amino acids, VFAs and some TAG pass via the blood to the liver. Most TAG moves through the lymphatic system to adipose tissue.
Hepatocytes transform nutrients into fuels and precursors for other tissues for example glycogen synthesis, TAG synthesis and protein synthesis.
Metabolism of Muscle
Skeletal muscle designed to work intermittently and on demand.
During rest or light activity, fatty acids, ketone bodies or blood glucose is utilised and produces CO2 as a waste product. During bursts of heavy activity, stored muscle glycogen is utilised and produced lactate. These all produce ATP. Lactate produced by muscle glycolysis is transported by the blood to the liver where it is converted to glucose by gluconeogensis. The blood carries glucose back to the muscle where it is stored as glycogen. In the glucose alanine cycle alanine produced in the muscle is transported to the liver where it is converted to pyruvate which is a substrate for gluconeogenesis.
Metabolism of the Brain
Adult brain uses mainly glucose as a fuel and has almost no stores of glycogen. During starvation when glucose is low, ketone body levels increase and these can be substituted for glucose.
Inborn Errors in the Brain
Citrullinaemia-has perinatal onset that leads to post natal mental retardation, stupor, coma and death. This is due to high levels of ammonia.
Maple syrup urine disease-lack of branched chain amino acid processing enzymes. Maple syrup odour of urine from alpha hydroxyl acids. Treatment in humans is to prescribe a diet free of BCAA.
Nitrogen Disposal and the Liver
Nitrogen disposal is a key function of the liver. Birds and reptiles produce uric acid to conserve water. Mammals produce urea. Ruminants can use organic non-protein nitrogen such as urea, amides and inorganic non-protein such as ammonium chloride, phosphate and sulphate. These can be toxic if levels are too high. If ammonia exceeds capacity of rumen bacteria to use, leads to poor nitrogen retention and is absorbed across rumen walls and excreted as nitrogen which requires energy. Blood urea originates from metabolism of tissue protein, deamination of excess amino acids and absorption of rumen NH3. In ruminants the urea can be recycled back to the rumen where microbes have urease activity to process urea and reduce the amount in blood. This can increase carbohydrate fermentation and increase propionate and butyrate levels.
Neurological complications that can result due to liver disease include failure to produce substances needed for energy and failure to clean toxins from blood.
Ketone Bodies
Water soluble circulating molecules that function as rapidly usable energy sources. Some examples include acetoacetate, beta-hydroxybutyrate and acetone. The breakdown of ketone bodies in the target organ does not occur by the reverse synthesis process. The breakdown of ketone bodies gives acetyl coA. Over-production of acetoacetate and beta hydroxybutyrate may be due to a lack of insulin and starvation and hypoglycaemia. Ketosis is the depletion of carbohydrates and mobilisation of FAs.
Blood Glucose Levels
Blood glucose rises after a meal and falls as the cell takes it up and metabolises it.
Propionate increases blood glucose as it is synthesised into glucose and stimulates the release of insulin.
Butyrate is not used in the synthesis of glucose but stimulates the release of insulin and glucagon that ultimately increases blood glucose.
Acetate is also not used for the synthesis of blood glucose but does not stimulate the release of insulin.
Glucose stimulates the release of insulin.
In response to high blood glucose, beta iselt cells secrete insulin which lowers blood glucose. in response to low blood glucose, alpha islet cells secrete glucagon which helps maintain blood glucose as a steady state. Both are peptide hormones.
Release of Insulin
Insulin release is triggered by glucose metabolism in the pancreatic cells. When glucose enters the cell via GLUT2 protein and undergoes glycolysis to become ATP.
The increase in ATP inhibits K+ channels causing membrane depolarisation. This opens voltage sensitive calcium channels. Intracellular calcium triggers exocytosis of secretory vesicles containing insulin.
Actions of Insulin
Increases: Glucose uptake in liver and muscle Glucose synthesis in liver and muscle Glycolysis and acetyl CoA production Fatty acid synthesis in the liver Triacylglycerols synthesis in adipose tissue
Decreases:
Glycogen breakdown in liver and muscle
Binding of Insulin
Binds to its protein kinase receptor. This increase in enzyme activity causes many downstream responses, It also causes activation of key protein phosphatases and altered activity of metabolic enzymes. Signals to muscle and adipose tissue to traffic GLUT4 to the membrane where the protein is released from vesicles.
Actions of Glucagon
Increases:
Glycogen breakdown in the liver
Gluconeogenesis in the liver
Fatty acid mobilisation in adipose tissue
Decreases:
Glycogen synthesis
Glycolysis in liver
Binding of Glucagon
G protein is activated, which activates adenylate cyclase which converts ATP to cAMP. cAMP activates protein kinase A which phosporylates a range of proteins that produce regulatory enzymes and increase blood glucose concentration.
Insulin-Glucagon Antagonism
In monogastrics, insulin promotes liver glycolysis via its action on regulatory enzymes which catalyse one direction pathways. It does this by dephosphorylating, increasing activity of these enzymes. Causes an increase in use of glucose as a fuel. PFK is stimulated by decreased levels of ATP and citrate. Glucagon slows liver glycolysis. It activates a protein kinase which phosphorylates these enzymes hence inhibiting them. Glucagon also promotes liver gluconeogenesis by activating regulatory enzymes in this pathway. Insulin when released also suppresses glucagon secretion via a paracrine effect on alpha cells. This is insulin-glucagon antagonism. Insulin activates a phosphodiesterase which decreases the concentration of cAMP. Glucagon uses cAMP activated protein kinases that to inhibit enzyme activity thus reducing cAMP which reduces glucagon activity.
Ruminant and Cat Glucose Source
Ruminants and cats gain little or no glucose from feed therefore they are heavily reliant on gluconeogenesis to increase blood glucose. Volatile fatty acids and glucogenic amino acids are used as substrates in the pathway. In ruminants after a meal insulin and glucagon both appear to rise. Insulin is released in response to amino acids and acetate. The effect of amino acids on the liver is marginal. Glucagon is released then for gluconeogenesis to prevent hypoglycaemia due to insulin.
Epinephrine
Is a catecholamine synthesised from tyrosine. When made in the brain, functions as a neurotransmitter. When norepinephrine or epinephrin are made by the adrenal medulla they act as hormones. Epinephrine increases glycogen breakdown in the muscle and liver, decreases glycogen synthesis, increases glucogenesis, increases glycolysis, increases fatty acid mobilisation, blocks insulin release.
Cortisol
Is a steroid hormone derived from is produced by the adrenal cortex and acts upon muscle, liver and adipose tissue and is relatively slow working. Cortisol acts upon adipose tissue in the hydrolysis of stored TAG and release of fatty acids which leads to increased glycerol which is used in the liver for glyconeogenesis. In the muscle tissue the breakdown of proteins leading to increase in amino acids which are used in the liver for gluconeogenesis. In the liver gluconeogenesis promoted.
Thyroxine
Similar to cortisol. T3 binds to a transcription factor called RXR/THR. Binds to DNA at specific base sequence in the promoter region of some genes. Alters transcription of genes with this sequence and can determine which genes are tuned on by transcriptomics. T3 stimulates production of mitochondrial proteins ad NaK ATPase pump.
Steroid Hormone Signalling
Peptide or amine hormones bind to the receptor on the outside of the cell and second messengers alter the activity of pre-existing enzymes. Steroid hormones bind to a receptor which enters the cells and acts in the nucleus. There are no second messengers. The hormone alters transcription of specific genes and alters the amount of newly synthesised proteins.
IP3
IP3 is a highly polar and is present in the cytosol. Its major effect is to open a calcium channels and to release calcium from intracellular stores within the endoplasmic reticulum.
DAG
DAG is a non-polar and resides in the membrane to interact with membrane bound proteins. DAG activates protein kinase C which control many proteins by ser/thr phosphorylation.
Calcium
Cytosol concentration kept low. Is pumped out of cells into intracellular stores. The cytosolic concentration can rise 100x when calcium channels open.
Second Messengers
Small molecules that transmit the signal by binding to protein targets. Some examples of second messengers include calcium, cAMP, PIP3.
PIP2
Can be phosphorylated by PI3 kinase to PIP3 which acts upon Protein Kinase B in the insulin cascade.
Metabolism in Fasting and Starvation
Mammalian fuel reserves are glycogen in the liver, muscle, TAG in adipose tissue and tissue protein. All of these can be degraded to provide energy.
Glycogen is used first but is depleted quickly. TAG provide alot of energy however can not be directly used to form glucose. Amino acids form tissue proteins are used to form glucose however structural proteins are degraded and is hence used as a last resort.
