Integration of Metabolism lect 6.pdf

Integration of Metabolism Professor Shivananda Nayak Professor of Biochemistry DR. SHIVANANDA NAYAK 1 Integration of Metabolism Objectives At the end of this lecture student should be able to : Explain the roles of the liver, muscle and adipose tissue in the mobilisation, inter-conversion, consumpt...

Integration of Metabolism Professor Shivananda Nayak Professor of Biochemistry DR. SHIVANANDA NAYAK 1 Integration of Metabolism Objectives At the end of this lecture student should be able to : Explain the roles of the liver, muscle and adipose tissue in the mobilisation, inter-conversion, consumption and storage of energy substrates Describe the integration of metabolism during fed and fasting conditions DR. SHIVANANDA NAYAK 2 Integration of Metabolism T h e o rga n i s m s p o s s e s s v a r i a b l e e n e rg y d e m a n d s ; h e n c e t h e supply is also equally variable. T h e c o n s u m e d m e ta b o l i c f u e l m ay b e ox i d i ze d t o C O 2 a n d H 2 O o r s t o re d t o m e e t t h e e n e rg y re q u i re m e n t s a s p e r t h e b o d y n e e d s. AT P s e r v e s a s t h e e n e rg y c u r re n c y o f t h e c e l l. MARCH 2024 DR. SHIVANANDA NAYAK Integration of major metabolic pathways of energy metabolism Glycolysis: Degradation of glucose to pyruvate (Lactate under anaerobic) generates 8 ATP. Fatty acid oxidation: Fatty acid (FA) oxidizes to Acetyl CoA. Energy is trapped in the form of NADH and FADH2 Amino acid degradation: When amino acids consumed more than the required, are degraded to meet the fuel demands of the body. The glucogenic amino acids can serve as the precursor for the synthesis of glucose via pyruvate or intermediates of TCA cycle. The ketogenic amino acids form the precursor for acetyl CoA. DR. SHIVANANDA NAYAK Citric acid cycle: Acetyl CoA is the common metabolite, produced from different fuel sources. It enters citric acid cycle and gets oxidized to CO2. Most of the energy is trapped in the form of NADH and FADH2. Oxidative phosphorylation: The NADH and FADH2, produced in different metabolic pathways, are finally oxidized in the electron transport chain, which is coupled with oxidative phosphorylation to generate ATP. Hexose monophosphate shunt: Concerned with the liberation of NADPH, which is utilized for biosynthesis of several compounds, including fatty acids and ribose sugar, which is an essential component of nucleotides. DR. SHIVANANDA NAYAK Gluconeogenesis: Many non-carbohydrate compounds serve as precursor for gluconeogenesis. Glycogen metabolism: Glycogen is the storage form of glucose, in liver and muscle. Glycogen serves as a fuel reserve to meet body needs for a brief period. The metabolic pathways, in general are controlled by four different mechanisms: 1.The availability of substrates 2.Covalent modification of enzymes 3.Allosteric regulation 4.Regulation of enzyme synthesis DR. SHIVANANDA NAYAK Integration of metabolism during fed state The various tissues and organs of the body work in a well-coordinated manner to meet its metabolic demands (usually 2-4 hours after food consumption) The insulin is the hormone that is responsible for controlling the metabolism in various organs of the human body DR. SHIVANANDA NAYAK 7 7 Liver It is specialized to serve as the body’s central metabolic clearing house. After a meal, the liver takes up the carbohydrates, lipids and amino acids, processes them and routes to other tissues. The major metabolic functions of liver, in absorptive state are: 1. Carbohydrate metabolism: Increased Glycolysis, glycogenesis and HMP shunt Decreased gluconeogenesis 2. Lipid metabolism: Increased fatty acid and triacylglycerol synthesis 3. Protein metabolism: Increased degradation of amino acids and protein synthesis. 8 Adipose tissue It is regarded as the energy storage tissue. 1.Carbohydrate metabolism: Increases uptake of glucose, glycolysis and HMP shunt 2. Lipid metabolism: Increased FA and TG synthesis. Degradation of TG inhibited. DR. SHIVANANDA NAYAK 9 9 Skeletal muscle: Major metabolic functions of skeletal muscle, in absorptive state are: 1.Carbohydrate metabolism: Uptake of glucose is higher and glycogenesis increased. 2. Lipid metabolism: FA taken up from the circulation. 3. Protein metabolism: Incorporation of amino acids into proteins is higher. DR. SHIVANANDA NAYAK 10 10 Brain 1. Carbohydrate metabolism: Glucose is the only source of fuel in an absorptive state. About 120 g of glucose is utilized per day. 2. Lipid metabolism: Free fatty acids cannot cross the blood-brain barrier; hence their contribution for the supply of energy to the brain is insignificant. DR. SHIVANANDA NAYAK 11 11 DR. SHIVANANDA NAYAK Integration of metabolism during fasting condition It is a metabolic stress, which imposes certain metabolic compulsions on the organism. The hyperglycemic hormones becomes active to maintain blood glucose and to provide energy to the human body DR. SHIVANANDA NAYAK 13 The metabolism is reorganized to meet the new demands of fasting. Glucose is the fuel of choice for brain and muscle. During fasting the carbohydrate is not sufficient to meet the requirements.  Protein meet the fuel demands of the body The triacylglycerol (TG) of adipose tissue is the predominant energy reserve of the body. Starvation associated with decreased insulin and increased glucagon. DR. SHIVANANDA NAYAK 14 Liver in starvation 1. Carbohydrate metabolism: Increased glycogen degradation & then gluconeogenesis Dietary fuel is unavailable and no liver glycogen remains to maintain blood glucose. There is complete dependence upon hepatic gluconeogenesis, primarily from lactate and alanine. 2. Lipid metabolism: FA oxidation increased and the TCA cycle cannot cope up with the excess production of acetyl CoA, so it is diverted to ketone body formation. The fuel demands of the brain are met by ketone bodies. DR. SHIVANANDA NAYAK 15 Glucose Production and Utilization in the Fasting State 16 Adipose tissue in starvation 1.Carbohydrate metabolism: Glucose uptake and its metabolism reduced 2.Lipid metabolism: Degradation of TG increased which leads to increased release of FA from the adipose tissue, which serves as fuel for various tissues (brain is an exception). Glycerol liberated during lipolysis is used for glucose synthesis by the liver. FA and TG synthesis completely stopped here. 17 Skeletal muscle in starvation 1.Carbohydrate metabolism: Glucose uptake and its metabolism are lowered. 2.Lipid metabolism: FA and ketone bodies are utilized as fuel by the muscle. Prolonged fasting adopted to utilize FA. 3.Protein metabolism: Muscle proteins are degraded and the amino acids are utilized for glucose synthesis by liver. Protein breakdown is reduced if the starvation prolonged. DR. SHIVANANDA NAYAK 18 18 Fate of Amino Acids From Muscle Protein Breakdown in Starvation 19 DR. SHIVANANDA NAYAK Brain in fasting In the early phase of starvation, the brain mostly dependent on glucose, supplied by liver gluconeogenesis. This, in turn, depends on the amino acids released from the muscle protein breakdown. The Ketones bodies play a central role in prolonged starvation, replacing glucose as the primary fuel for the brain and signaling a reduction in protein catabolism Ref: Essentials of Biochemistry DR. SHIVANANDA NAYAK 21 21 DR. SHIVANANDA NAYAK 22 Wish you all the best Dr. Shivananda Nayak