Summary of Metabolic Pathways

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Presentation transcript:

Summary of Metabolic Pathways

Metabolic Profile: Brain Fuel(s) - glucose is prime fuel uses ~120g/day Fuel use(s) - active transport (Na+, K+ ), biosynthesis Glucose uptake - transporter half-saturated at 1.6 mM normal blood glucose level ~5 mM (90mg%) hexokinase saturated at 0.5 mM hypoglycemic danger level 2.2 mM (40mg%) Main metabolic pathways - totally aerobic metabolism glycolysis, citric acid cycle, ETS

Metabolic Profile: Skeletal Muscle Fuel(s) - Resting muscle - fatty acids Highly-active muscle - glucose from glycogen produces lactate Fuel use(s) - contraction, active transport (Ca2+) Main metabolic pathways - Resting muscle (aerobic) fatty acid oxidation, citric acid cycle, ETS Highly-active muscle (anaerobic) glycogenolysis, glycolysis

Metabolic Profile: Heart Muscle Fuel(s) - main fuel fatty acids Fuel use(s) - contraction, active transport (Ca2+) Main metabolic pathways - totally aerobic metabolism fatty acid oxidation, citric acid cycle, ETS

Metabolic Profile: Adipose Tissue Fuel(s) - major fuels glucose, fatty acids Fuel use(s) - biosynthesis of triacylglycerols, fatty acid synthesis (high blood glucose) Main metabolic pathways - glycolysis, fatty acid oxidation, citric acid cycle, ETS, fatty acid synthesis, triacylglycerol synthesis, lipolysis

Metabolic Profile: Kidney Fuel(s) - major fuels glucose, fatty acids Fuel use(s) - active transport, biosynthesis (glucose) Main metabolic pathways - Normal conditions - glycolysis, fatty acid oxidation, citric acid cycle, ETS During starvation - gluconeogenesis

Metabolic Profile: Liver Fuel(s) - major fuel fatty acids Fuel use(s) - biosynthesis of glucose, fatty acids, glycogen, triacylglycerols, cholesterol, bile salts, proteins, urea Main metabolic pathways - metabolic hub Carbohydrate - incoming - glycolysis, glycogenesis, lipogenesis, citric acid cycle, ETS Low blood glucose - glycogenolysis, gluconeogenesis Lipid - incoming - fatty acid oxidation, citric acid cycle, ETS, cholesterol synthesis, ketone body synthesis Surplus fuel - fatty acid and triacylglycerol synthesis Amino acids - protein synthesis Synthesis of nitrogenous compounds, glucose, urea

Tissue Interrelationships: Liver as Fuel Provider for Other Tissues Glucose provider - glycogenolysis, gluconeogenesis Fatty acid provider Excess fuel converted to triacylglycerols then VLDLs Provide fatty acids to other tissues or for storage in adipose tissue Ketone body provider Soluble form of fatty acid fuel Produced when blood glucose level low

Tissue Interrelationships: Liver and Skeletal Muscle Cori Cycle

Tissue Interrelationships: Liver and Skeletal Muscle Alanine-Glucose Cycle

Glucagon and Epinephrine Mechanism of Hormone Action: Glucagon and Epinephrine adenylyl cyclase hormone hormone binds to receptor and stimulates adenylyl cyclase ATP cyclic AMP receptor adenylyl cyclase catalyzes synthesis of secondary messenger (cAMP) protein kinase phosphorylated proteins Glucagon (liver) Inhibits glycogen synthase glycogenesis (–) Stimulates glycogen phosphorylase glycogenolysis (+) Inhibits phosphofructokinase glycolysis (–) Stimulates fructose 1,6-phosphatase gluconeogenesis (+) Epinephrine (liver) cAMP stimulates protein kinase to catalyze phophorylation of key proteins Inhibits glycogen synthase glycogenesis (–) Stimulates glycogen phosphorylase glycogenolysis (+) Glucagon and Epinephrine (adipose tissue) Inhibits phosphofructokinase glycolysis (–) Stimulates fructose 1,6-phosphatase gluconeogenesis (+) Epinephrine (skeletal muscle) Stimulates lipase lipolysis (+) Inhibits glycogen synthase glycogenesis (–) Stimulates glycogen phosphorylase glycogenolysis (+) Stimulates phosphofructokinase glycolysis (+)

Mechanism of Hormone Action: Insulin Insulin binds to receptor Stimulates synthesis of secondary messenger (inositol triphosphate, IP3 ) IP3 activates protein kinase that in turn catalyzes phosphorylation of key enzymes Processes and enzymes affected (take in and use fuel) Stimulates glucose uptake (liver, muscle, adipose tissue) Stimulates glycogen synthase (liver and muscle) glycogenesis (+) Inhibits glycogen phosphorylase (liver and muscle) glycogenolysis (–) Stimulates phosphofructokinase glycolysis (+) Inhibits fructose 1,6-bisphophatase (liver) gluconeogenesis (–) Stimulates fatty acid synthesis (liver) lipogenesis (+) Inhibits hormone-sensitive lipase (adipose cells) lipolysis (–)

Combined Effects of Insulin: The well-fed state

Combined Effects of Glucagon: The fasting state

Interplay between insulin and glucagon

Normal Daily Cycle for Glycogen

Starvation: First Week

Glucose Production by Liver and Kidney During First 10 Days of Fasting

Starvation: Six Weeks

Amount formed or consumed Fuel Metabolism in Starvation Amount formed or consumed in 24 hours (grams) Fuel exchanges and consumption 3rd day 40th day Fuel use by the brain Glucose 100 40 Ketone bodies 50 100 All other use of glucose 50 40 Fuel mobilization Adipose-tissue lipolysis 180 180 Muscle-protein degradation 75 20 Fuel output of the liver Glucose 120 40 Ketone bodies 150 150 Fuel output of the kidney 30 40

Metabolic Adjustment by the Liver During Prolonged Fasting or in Uncontrolled Diabetes