Lecture 4.1 - Energy Storage - Glycogen and Lipids PDF

Nutrients of human metabolism: ◦Carbohydrates, lipids and proteins serve as fuel molecules for the human body. ◦Absorbed end products: ‣ Carbohydrates - monosaccharides - most important fuel for brain and RBCs (use of glucose) ‣ Lipids - monoacylglycerol and long-chain...

Nutrients of human metabolism: ◦Carbohydrates, lipids and proteins serve as fuel molecules for the human body. ◦Absorbed end products: ‣ Carbohydrates - monosaccharides - most important fuel for brain and RBCs (use of glucose) ‣ Lipids - monoacylglycerol and long-chain fatty acids ‣ Proteins - peptides Carbohydrates: ◦Contain carbon, hydrogen and oxygen atoms ◦Energy source - glucose may have a different fate depending on what is is needed for ◦Includes - sugar, fruits, vegetables, fibres and legumes Glucose: ◦Most important fuel source for life ◦Preferred energy source for nervous system during initial physical activity (ketone bodies used in the brain) ◦Lack of glucose in the brain can lead to neurological issues ◦Essential building block - can be found in cell membranes ◦Small quantities stored ◦Glucose cannot enter a cell by simple diffusion ◦Glucose transport (GLUT) molecules (transporters) - insulin presence activates the GLUT transporters ◦Glucose homeostasis requires a continuous balance between glucose diffusion, storage and metabolism ◦4 Processes in metabolism of glucose: ‣ Glycolysis, glycogenesis, gluconeogenesis and glycogenolysis Storage of glucose - glycogen: ◦Glucose can be stored as glycogen - a polymer of glucose ◦Efficient - large molecule, minimal osmotic effect ◦The liver can supply about 16 hours of glucose ‣ Muscle ~ 400g ‣ Liver ~ 75g  Glycogen synthesis - glycogenesis: ◦The anabolic hormone insulin initiates glycogenesis ◦Hexokinase is an important enzyme Glycogen degradation - glycogenolysis: ◦Glycogenolysis provides glucose during short periods of fasting, between meals, during sleep etc. ◦Glucagon and the adrenal catecholamines epinephrine and norepinephrine regulate glycogenolysis ◦The pathway is not a reversal of the synthetic pathway. Regulation of glycogen metabolism: ◦Synthesis - glycogen synthase - insulin deactivates glycogen phosphorylase and activates glycogen synthase ◦Degradation - glycogen phosphorylase ◦Allosteric control from adrenaline, insulin and glucagon - hormones Regulation of glucose - overview:  Glycogen - overview: Disorders of glycogen metabolism: ◦Incidence 1 in 20,000 - 1 in 40,000 ◦Arise from deficiency or dysfunction of enzymes of glycogen metabolism ◦Liver and/or muscle affected ◦Abnormal glycogen structure ◦Excess glycogen storage -> tissue damage ◦Diminished glycogen -> hypoglycaemia, poor exercise tolerance Glycogen metabolism in the clinical context: ◦Von Gierke disease is a condition in which the body cannot break down glycogen. This disorder is caused by a deficiency of the enzyme glucose 6-phosphate, leading to accumulation of glucose -phosphate intracellularly. Von Gierke disease: ◦1 in 100,000 births, inherited as autosomal recessive traits ◦Signs and symptoms: ‣ Hypoglycemia and lactic acidosis (seizures) ‣ Enlarged liver (hepatomegaly) ‣ Cerebral damage (severe) Glycolysis: ◦Enzymatic catabolism of the (carbon) sugar glucose into two (3 carbon) molecules of pyruvate +2 ATPs ◦Glycolysis is the anaerobic metabolism of glucose ◦Important during the initial phase of physical activity or in limited oxygen availability ◦Ten steps reaction in order to form ATP  ◦Glucose is trapped by phosphorylation - Hexokinase (1) ◦Rate limiting enzyme - phosphofructokinase (3) ◦Energy-requiring phase - two ATP are spent (1,3) ◦Energy-releasing phase - four ATP produced (7,10) Gluconeogenesis: ◦Synthesis of new glucose from non-carbohydrate substrates such as lactate, pyruvate, glycerol and alanine ◦Occurs in the liver and kidney cortex ◦Gluconeogenesis occurs as part of the response to stress situations (e.g. fasting, starvation, prolonged exercise) and is largely under hormonal control. Regulation of gluconeogenesis: Lipid storage: ◦Fatty acids (FA) are stored primarily in adipocytes (mainly in the abdominal cavity) as triacylglycerol ◦Triacylglycerol must be hydrolysed to release the fatty acids ◦Triacylglycerols are highly calorific - more efficient in producing energy ◦Hormonal control: ‣ Insulin -> storage ‣ Glucagon, adrenaline, cortisol, GH -> mobilisation Lipolysis - mobilisation of FA: ◦Adipocytes -> release triacylglycerol -> glycerol and non-esterified fatty acids ◦Regulation: ‣ Insulin -> inhibits HSL ‣ Epinephrine, norepinephrine, ACTH and glucagon -> activates HSL  Fatty acid oxidation: ◦Beta-oxidation source of energy during periods of fasting and exercise - fatty acids produce energy ◦Supply energy when glycogen and gluconeogenic precursors become scarce ◦FA activates as FA-CoA derivative ◦Occurs in the mitochondria ◦4 ATP per round - beta-oxidation is very efficient Lipogenesis - FA synthesis: ◦Fatty acids are synthesised from acetyl-CoA ◦Requires ATP and NADPH ◦Occurs in the cytoplasm of liver cells ◦Acetyl-CoA comes from mitochondria (transport mechanism across mitochondrial membrane) FA synthesis/lipid storage: ◦AMPK is an allosteric regulator Lipogenesis vs lipolysis: