Integrated Tissue Metabolism 2024 PDF

Integrative Tissue Metabolism Dr. Alawi Habara MBBS, M.Sc. (Medical Genetics), Ph.D. (Molecular & Translational Medicine). Assistant Professor College of Medicine Department of Biochemistry IAU Learning objectives Be able to understand the difference in fuel metabolism during different body st...

Integrative Tissue Metabolism Dr. Alawi Habara MBBS, M.Sc. (Medical Genetics), Ph.D. (Molecular & Translational Medicine). Assistant Professor College of Medicine Department of Biochemistry IAU Learning objectives Be able to understand the difference in fuel metabolism during different body states (well-fed, fasting, and starvation). Understand the effect of hormones (insulin & glucagon) on metabolism. Understand the heart muscle energy production Understand the skeletal muscle energy system Red blood cells and glutathione production 2 The liver The liver is extremely essential for overall body homeostasis. It does that through, several biochemical processes and without them, we cannot maintain life. The liver is the central organ for carbohydrate, lipid, and protein metabolism in humans. The liver act as a processor, and distributor for almost all nutrients. The liver is capable of both storing (glycogen) and producing glucose (gluconeogenesis). It plays a key role in maintaining the normal plasma glucose level. Additionally, the liver can synthesize fatty acids and protein. 3 The well-fed state: Lipogenic liver In the fed state Glucose level is elevated. This will lead to the release of insulin from the pancreas. Insulin will lead to increase glucose intake from the tissue that has insulin-dependent transport channels e.g. GLUT4 in muscles and adipose tissue. The liver will take glucose in an independent manner (GLUT2). Insulin in the liver will induce the following pathways: Glycolysis. Glycogenesis (the liver can store 5% of its weight as glycogen). Lipogenesis (the liver can store a small amount of fat less than 5% of its weight, under normal healthy conditions) Protein synthesis. TAG from the diet will ultimately be packed as chylomicrons in the small intestine and transported via the lymphatic system, then the bloodstream to peripheral tissue. Amino acids absorbed will go to the liver, where they will be used for protein synthesis. Under fed conditions, the excess amino acid is converted into fatty acid; Carbons of amino acids go into fatty acid and nitrogen to urea cycle. 4 The well-fed state: Lipogenic liver Metabolic effect of insulin Target ↑ Insulin, ↓ Glucagon in liver (G=activate, R=inhibit) Glucose Glucose uptake Glucokinase Glycolysis PFK-1 PFK-2 Pyruvate kinase Pyruvate dehydrogenase HMS G6PD Glucose Glycogenesis Glycogen Synthase FA synthesis Acetyl-CoA Carboxylase Fatty acid synthase Glycogenesis Glucose Glucose Glycogen Cholesterol HMG CoA Reductase Obtained and modified from Table 23-3 Principle of biochemistry e6, 2012 Amino acid Glycolysis HMS Insulin receptor Protein Pyruvate Under the fed condition; TAG Chylomicrons synthesis Cholesterol Resting skeletal muscle; use glucose as an energy TAG will be packed as Lipogenesis source. chylomicrons in the small Exercising skeletal muscle uses glucose, fatty acid, and Acetyl CoA TAG glycogen storage. intestine and transported via the The production of Glucose lymphatic system then to the TAG requires Metabolic effect of insulin Target bloodstream to peripheral tissue. Insulin NADPH. Where in muscle (G=activate, receptor TCA will the liver get R=inhibit) cycle this? Glucose uptake GLUT4 insulin in Target Glycogen TCA adipose (G=activate, cycle Glycolysis PFK-1 R=inhibit) PFK-2 Pyruvate kinase Glucose uptake GLUT4 Glucose TAG VLDL Pyruvate dehydrogenase FA synthesis Acetyl-CoA Carboxylase TAG Fatty acid synthase Glycogenesis Glycogen Synthase Release TAG from CMs + Lipoprotein Lipase 5 VLDL The fasting state: Glucogenic liver During fasting, the liver becomes the primary source of glucose. Glycogen storage is utilized to release glucose. After the depletion of glycogen, gluconeogenesis becomes the source of glucose. Substrates for gluconeogenesis are alanine from muscle, glycerol from adipose tissue, and lactate from anaerobic glycolysis. Fatty acid is mobilized from adipose tissue and used for muscle energy production and in the liver for energy and ketone body production. 6 Fasting state: Glucogenic liver Metabolic effect of glucagon Target (Green=activate, (Green=activate, Red=inhibit) Red=inhibit) ↑ Glucagon Glucose Low plasma Glycogen breakdown (liver) Glycogen phosphorylase glucose Fatty acid mobilization (Adipose Hormone sensitive lipases Ketone bodies tissue) Gluconeogenesis (liver) Fructose 2,6- biphosphatase Glycolysis (liver) PFK-1 PFK-2 Glycogenolysis Glucose Pyruvate Kinase Ketogenesis Glycogen Glucose-6-phosphate Glucose Obtained and modified from Table 23-3 Principle of biochemistry e6, 2012 Amino Protein acid TCA Pyruvate cycle Glycerol Acetyl CoA TAG Ketone bodies TCA Ketone bodies Fatty cycle acid Ketogenesis Fatty acid TCA Protein 7 Prolong fasting Glycogen storage has already been depleted. Gluconeogenesis is the main source of glucose Muscle protein degrades to give amino acids for gluconeogenesis Glycerol from adipose tissue. Lactate from anaerobic glycolysis. Ketone bodies start to appear more significantly in blood and slowly being used by the brain 8 Starvation Start from 72 hours from the last meal. Glycogen storage has already been depleted. Gluconeogenesis continues producing glucose. Muscle protein degradation to give amino acids for gluconeogenesis will continue until around 7 days of starvation after that muscle protein degradation will slow down. Glycerol from adipose tissue will continue. Lactate from anaerobic glycolysis will continue. Brain is adopted for using ketones body during starvation. 9 The bi-enzymatic activity of PFK-2/FBPase-2 Fed state and fasting state Obtained from https://next.amboss.com/us/search?q=f ed+state&v=overview&m=nvb70D 10 Adipose tissue in fed and fasting state Glucagon receptors are in the liver β-Adrenergic receptors are in the liver and muscle Obtained from 11 https://next.amboss.com/us/search?q=fed+state&v=overview&m=yaXdM9 Skeletal Muscle Skeletal muscles are specialized to generate ATP in multiple ways Free ATP Carnitine phosphate (Phosphagen system) Glycolysis Aerobic glycolysis Anaerobic glycolysis Oxidative phosphorylation Glucose Fatty acid Ketone bodies 12 Muscle energy systems The (Phosphagen system) Free ATP that ATP gets republished by converting 50m sprint The amount of ADP to ATP using creatine phosphate. This energy stored as is enough for about 15 sec of muscle Oxidative Phosphorylation 5Km free ATP in the activity. Then the CP storage is depleted. muscle is enough marathon Weight-lifting for about 3 sec Fatty acid of muscle % of energy activity β-Oxidation Glycolysis Extreme and long muscle activity TCA requires a huge amount of ATP for 2 ATP Aerobic cycle that type of activity; muscles get Pyruvate Acetyl CoA their ATP for this type of activity from oxidative phosphorylation of acetyl CoA (which can be from glucose or fatty acid source) Lactate 500m run The muscle now needs an additional Time Glucose source of ATP, and that’s when Anaerobic glycolysis starts. The lactate produced in anaerobic 6 ATP glycolysis diffuses to the bloodstream where it goes to the Cori liver and gets converted to glucose Cycle (Cori cycle) and that glucose return to the muscle to be utilized again for 13 anaerobic glycolysis. Heart muscle Fatty acid is the primary source of energy in cardiomyocytes. 60-90% of ATP is generated from the oxidation of long-chain fatty acids 10-30% is from the oxidation of glucose ATP from Lactate ketone bodies and amino acids under normal condition is minor Unlike skeletal muscle, the heart can not produce energy from anaerobic glycolysis. Can not store lipid or glycogen in a significant amount. 14 Red blood cells (RBCs) RBCs do not have mitochondria or organelles and therefore can not use oxidative phosphorylation for energy Can only use glucose for energy and is entirely anaerobic It uses HMS to produce NADPH which is very important to produce glutathione (anti-oxidant) Oxidant stress: Oxidative drug Fava infection Glucose G6P NADP GSH H2O2 G6P Glucose 6 phosphate Glutathione Glutathione Glycolytic pathway dehydrogenase reductase peroxidase 6PG= 6-phosphogluconate 6PG NADPH GSSG H2O GSH= Glutathione GSSG= Oxidized Glutathione (Glutathione 2ATP disulfide) H2O2= Hydrogen peroxide (harmful, leads to 2Lactate oxidative stress) 15 Thank you, Any questions? Contact [email protected] Office: 031-33-31126 Office location: Building A72 college of medicine, Biochemistry department office #3006 16 References Ritterhoff J, Tian R. Metabolic mechanisms in physiological and pathological cardiac hypertrophy: new paradigms and challenges. Nature Reviews Cardiology. 2023 Dec;20(12):812-29. 17