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Brain Needs in Different Metabolic states Learning Objectives At the end of the lecture, the students should be able to • Describe the stats of the brain. • Explain the mechanism and mode of metabolism in a post aborptive state. • Discuss the mechanism and mode of metabolism in a post aborptive state. • Describe the brain in postabsorptive and fasting states. • Explain the removal of ammonia and glutamate from the brain. Definition… • Metabolism – the sum of all the chemical processes whereby _______ is made available and used by the cells of the body • Energy– the ability to do work Energy is used for… • Adult human require 10 – 12 MJ (2400 – 2900 Kcal) (1 kcal = 4.18 Joule ) from metabolic fuel each day. • 40 -60 % from carbohydrate • 30 -40 % lipids • 10 – 15 % proteins. • In starving state glucose spared for use by the central nervous system and erythrocytes. ENERGY METABOLISM AT THE ORGAN LEVEL • Although the brain represents only 2% of the body weight: • It receives 15% of the cardiac output, • 20% of total body oxygen consumption. The brain is extremely sensitive to hypoxia, and occlusion of its blood supply produces unconsciousness in as short a period as 10 seconds. • 25% of total body glucose utilization. • The brain’s consumption of glucose and oxygen are constant regardless of resting/ sleeping or active/ waking Major features of metabolism of the principal organ • Liver: Service for the other organs and tissues major pathways: gluconeogensis, beta oxidation, ketogensis, urea, uric and bile formation, cholesterol synthesis. • Brain: coordination of nervous system Major pathways: Glycolysis, amino acid metabolism • Adipose tissues: Storage and breakdown of TG Esterification of fatty acids and lipolysis, lipogensis • Muscle: • Erythrocytes: • Kidney : Brain Metabolism • High energy requirements (~1.0 mg/kg/min) • Low energy reserves • The energy is needed to maintain the ionic gradient across nerve membranes. • The glucose transporter, GLUT-1, is enriched in the brain capillary endothelial cells and mediates the facilitated diffusion of glucose through the blood brain barrier. • Most of the glucose is metabolized to pyruvate, which enters the mitochondria of neurons and glia and is converted to acetyl-CoA before entering the TCA cycle. • Only about 13% of glycolytic pyruvate is converted to lactate under normal condition. Name GLUT1 GLUT2 [edit] Classes II/III Distribution Notes Is widely distributed in fetal tissues. In the adult, it is expressed at highest levels in erythrocytes and also in the endothelial cells Levels in cell membranes are of barrier tissues such as the blood –brain barrier. However, it is increased by reduced glucose levels and decreased by increased responsible for the low-level of basal glucose uptake glucose levels. required to sustain respiration in all cells. Is expressed by renal tubular cells and small intestinal epithelial cells that transport glucose, liver cells and pancreatic beta cells. All three monosaccharides are . transported from the intestinal mucosal cell into the portal circulation by GLUT2 Is a high capacity and low affinity isoform GLUT3 Expressed mostly in neurons (where it is believed to be the main glucose transporter isoform), and in the placenta. Is a high-affinity isoform GLUT4 Found in adipose tissues and striated muscle (skeletal muscle and cardiac muscle. Is the insulin-regulated glucose transporter. Responsible for insulin-regulated glucose storage 1. Postabsorptive state Glucose + Amino acids -> transport from intestine to blood Dietary lipids transported -> lymphatic system -> blood Glucose stimulates -> secretion of insulin Insulin: signals fed state stimulates storage of fuels and synthesis of proteins high level -> glucose enters muscle + adipose tissue (synthesis of TAG) stimulates glycogen synthesis in muscle + liver suppresses gluconeogenesis by the liver accelerates glycolysis in liver -> increases synthesis of fatty acids-> accelerates uptake of blood glucose into liver -> glucose 6-phosphate more rapidly formed than level of blood glucose rises -> built up of glycogen stores Insulin Secretion –Stimulated by Glucose Uptake Postabsorptive State -> after a Meal 2. Early Fasting State Blood-glucose level drops after several hours after the meal -> decrease in insulin secretion -> rise in glucagon secretion Low blood-glucose level -> stimulates glucagon secretion of α-cells of the pancreas Glucagon: -> signals starved state -> mobilizes glycogen stores (break down) -> inhibits glycogen synthesis -> main target organ is liver -> inhibits fatty acid synthesis -> stimulates gluconeogenesis in liver -> large amount of glucose in liver released to blood stream -> maintain blood-glucose level Muscle + Liver use fatty acids as fuel when blood-glucose level drops Early Fasting State -> During the Night 3. Refed State Fat is processed in same way as normal fed state First -> Liver does not absorb glucose from blood (diet) Liver still synthesizes glucose to refill liver’s glycogen stores When liver has refilled glycogen stores + blood-glucose level still rises -> liver synthesizes fatty acids from excess glucose Prolonged Starvation Well-fed 70 kg human -> fuel reserves about 161,000 kcal -> energy needed for a 24 h period -> 1600 kcal - 6000 kcal -> sufficient reserves for starvation up to 1 – 3 months -> however glucose reserves are exhausted in 1 day Even under starvation -> blood-glucose level must be above 40 mg/100 ml 6 F atty acids are attached to lipoproteins and do not pass the blood brain barrier as fuel substrates. • The lactate is used for energy metabolism in adult brain, but this remains somewhat controversial. • While glucose is the preferred energy substrate, neurons and glia will metabolize ketones for energy under fasting-induced reductions of blood glucose. Ketone bodies • • • • Consisting of acetoacetate, and β -hydroxybutyrate (β-OHB) Catabolism of fat in the liver Concentration in blood is inversely related to that of glucose. Ketone bodies are transported into the brain through the bloodbrain barrier monocarboxylic transporters (MCTs), whose expression is regulated in part by circulating ketone and glucose levels. • β-OHB is the predominant • Rapidly oxidized to acetyl-CoA in the mitochondria through an enzymatic series involving 3-hydroxybutyrate dehydrogenase, • SCOT (succinyl-CoA-acetoacetate-CoA transferase), and mitochondrial acetyl-CoA thiolase • Acetone is a non-enzymatic byproduct of ketone body synthesis and is largely excreted in the urine or exhaled from the lungs. • Ketone bodies are more energetically efficient than either pyruvate or fatty acids because they are more reduced (greater hydrogen/carbon ratio) than pyruvate and do not uncouple the mitochondrial proton gradient as occurs with fatty acid metabolism. In contrast to glucose, ketone bodies by-pass cytoplasmic glycolysis and directly enter the mitochondria where they are oxidized to acetyl-CoA The amount of acetyl-CoA formed from ketone body metabolism is greater than that formed from glucose metabolism. ketone body metabolism can also reduce production of damaging free radicals • • • Glycogen Metabolism • Primarily stored in astrocytes • Levels in brain are low compared to liver and muscle • Turnover rate is very rapid; its synthesis and breakdown are regulated by the two key enzymes glycogen phosphorylase and synthase. • Glycogen levels are tightly coupled to synaptic activity • During anesthesia they rise sharply • Regulated in Astrocytes by Norepinephrine and Vasoactive Intestinal Peptide. Glutamate Removal • The brain's uptake of glutamate is approximately balanced by its output of glutamine • Glutamate entering the brain takes up ammonia and leaves as glutamine • The glutamate–glutamine conversion in the brain—the opposite of the reaction in the kidney that produces some of the ammonia entering the tubules—serves as a detoxifying mechanism to keep the brain free of ammonia. Ammonia Removal • Ammonia is very toxic to nerve cells, and ammonia toxication is believed to be a major cause of the bizarre neurologic symptoms in hepatic coma. • Ammonia may be toxic to the brain in part because it reacts with ketoglutarate to form glutamate. The resulting depleted levels of ketoglutarate then impair function of the tricarboxylic acid (TCA) cycle in neurons. All protein amino acids except lysine, theronine, proline participate in transmanination. • Transmamination intercoverts pairs of alpha amino acids and alpha keto acids. • Transfer of amino nitrogen to alpha ketoglutrate form L-glutmate, By glutmate dehydrogenase ammonia produced. • Glutamine + NH4 and glutaminase form glutamate. Stroke • The blood supply to a part of the brain is interrupted, • There are two general types of strokes: hemorrhagic and ischemic. • Hemorrhagic stroke occurs when a cerebral artery or arteriole ruptures. • Ischemic stroke occurs when flow in a vessel is compromised by atherosclerotic plaques on which thrombi form. • It has now become clear ischemia reduces glutamate uptake by astrocytes, and the increase in local glutamate causes excitotoxic damage and death to neurons. • In experimental animals and perhaps in humans, drugs that prevent this excitotoxic damage significantly reduce the effects of strokes. • In addition, clot-lysing drugs such as t-PA are of benefit. • Both antiexcitotoxic treatment and (tissue plasmogen activator) t-PA must be given early in the course of a stroke to be of maximum benefit, • it is important to determine if a stroke is thrombotic or hemorrhagic, since clot lysis is contraindicated in the latter. References • Harpers Biochemistry • Lippincott Review of biochemistry • Medical Biochemistry by Chatterji THANK YOU