Intermediary metabolism Eva Samcová
Metabolic roles of tissues Four major tissues play a dominant role in fuel metabolism : liver, adipose, muscle, and brain. These tissues do not function in isolation. Communication between tissues is mediated by the nervous systém, by the availability of circulating substrates, and by variation in the levels of plasma hormones. The integration of energy metabolism is controlled by the actions of two peptide hormones, insulin, and glucagon (response to changing substrate levels) with catecholamines epinephrine and norepinephrine (response to neural signals).
Liver Liver lies immediately under the diaphragm. It is supplied with blood from below through two major vessels: the hepatic artery (20% of blood) and the hepatic portal vein which brings the substrates (soluble in water) absorbed from the intestinal tract including stomach into the blood and then directly to liver. Pancreatic vein (insulin, glucagon) Liver consumes 20 30% of total oxygen consumption
Functions of the liver The uptake of nutrients delivered from the digestive tract via portal vein The synthesis, storage, interconversion and degradation of metabolite The regulated supply of energy-rich intermediates The detoxification of harmful compounds by biotransformation The excretion of substances with the bile; synthesis and degradation of many blood plasma constituents
Carbohydrate metabolism in the liver- fed conditions Concentration in portal vein after a meal up to 10 mmol/l GLUT-2 type glucose transporter not responsive to insulin, relatively high K m (rate and direction of movement of glucose through hepatocyte membrane are determined by concentration inside and outside the cell) Glucokinase (K m = 12 mmol/l) x hexokinase 0.1 mmol/l Any increase in glucose concentration against blood conc. leads to proportional increase in the rate of phosphorylation by glucokinase.likewise any decrease in glucose conc. leads to proportional decrease in the rate of phosphorylation. Thus liver uses glucose at significant rate only when blood glucose level is greatly elevated. The overall result is that when glucose conc. outside the hepatocyte rises, glucose will be rapidly taken into cells and phosphorylated.
Carbohydrate metabolism in the liver- fed conditions The presence of high-k m glucose transporter and high-k m glucokinase do not enable the hepatocyte to take up unlimited quantities of glucose as G-6-P There are specific mechanisms for stimulating the disposal of Glu-6-P Glycogen synthesis (activation of glycogen synthase by insulin and glucose) Glycolysis metabolizes glucose to pyruvate TCA, some released after conversion to lactate. But minor energy source for liver.
Metabolic Fate of G6P
Carbohydrate metabolism overnight fasted conditions Glycogen breakdown (glycogenolysis), controlled by reciprocal activation of glycogen phosphorylase by glucagon, adrenalin, noradrenalin, catecholamines. Glu-1-P produced by glycogenolysis is in equilibrium with Glu-6-P (enzyme phosphoglucomutase). Formation of glucose from Glu-6-P is produced by enzyme Glu-6-phosphatase (membrane ER) 12/2/12
Carbohydrate metabolism in the liver Synthesis of glucose gluconeogenesis Substrates : lactate, alanine, glycerol Hepatic gluconeogenesis can be also stimulated by increase in the supply of substrate from other tissue (after physical exercise-lactate, starvation-glycerol) and by hormones (glucagon) Glucose paradox (gluconeogenesis after meal) The pentose phosphate pathway alternative fate for Glu-6-P, conversion to five-carbons sugars (ribose-5- P for synthesis of nucleic acids) Formation of NADPH for reductive synthesis
Fat metabolism in the liver The metabolism of lipids in the liver is closely linked to metabolism of carbohydrates and amino acids. The pathwayof FA oxidation diverges from that of glycerolipid synthesis when acyl-coa enters the mitochondrion for oxidation. Carnitine-palmitoyl transferase-1 (CPT-1). Activity of this enzyme is strictly regulated by means of compound malonyl-coa (potent inhibitor). This role of malonyl-coa provides a vital link between carbohydrate and fat metabolism.
Fat metabolism in the liver The liver converts glucose (Glc) via Acetyl-CoA into fatty acids (FA) - cytosol. FA and chylomicrons are used as a sources neutral fats and phospholipides. In humans FA synthesis from other molecules (Glc) is usually small in comparison with dietary fatty acid intake. VLDL are formed in smooth ER of hepatocytes. High concentration of acetyl-coa (postabsorptive state, starvation) as a result of β-oxidation of FA in mitochondrion great amount of ketone bodies : acetoacetate, 3-hydroxybutyrate and acetone. 12/2/12
Fat metabolism in the liver Cholesterol has two sources, the diet and de novo synthesis (in liver significant amount). Some cholesterol is required for synthesis of bile acids, some for cell membranes, some is stored in the form of lipids droplets in esterified form. The rest in free and esterified form in VLDL (to supply another tissues) The liver also degrades lipoprotein complexes (with cholesterol and cholesterol esters) taking up from the blood.
Amino acid metabolism in the liver Our bodies do not continuously accumulate or lose protein in a net sense. The rate of AA oxidation in the body must therefore balance the rate of entry of dietary protein (70-100g per day) Catabolism of AA occurs predominantly in the liver with exceptions (branched chain amino acids in muscles) AA oxidation provides ½ of the liver s energy requirements It is also the only organ capable of eliminating the nitrogen from amino acids by urea cycle
Starve-Feed Cycle The starve-feed cycle allows a variable fuel and nitrogen consumption to meet a variable metabolic and anabolic demand. Feed refers to intake of meals (variable fuel) after which we store the fuel in the form of glycogen and fat, to meet our metabolic demand while we fast. ATP is energy-transferring agent in this cycle.
Well-Fed State Amino acids Dietary proteins are hydrolyzed in the intestine (some of them are used like energy source here : Asp, Asn, Glu, Gln Ala, Lac, citrul, Pro into the portal blood) Liver lets most of AA coming from intestine pass through, for synthesis of proteins in peripheral tissue, thanks to high K m.high K m allows to AA to be in excess without catabolism. Utilization of AA for proteosynthesis (much lower K m for trna-charging enzymes) Excess of AA can be oxidized to CO 2, water, urea, or metabolites can be used as substrates for lipogenesis
Well-Fed State - glucose Glucose glycogen (glycogenesis), pyruvate, lactate (glycolysis), for pentose phosphate pathway (NADPH) Much of glucose from intestine passes through liver to reach other organs (brain, testis, RBC, renal medulla, AT) Number of tissues produce lactate and pyruvate from circulating glucose, which are taken up by liver, and fat is formed lipogenesis) In well-fed state liver does not engage in gluconeogenesis Cori cycle is interrupted
Well-βFed State fat Glucose, lactate, pyruvate and AA support hepatic lipogenesis. Fat formed from these substrates is released in the form of VLDL Chylomicrons, VLDLs circulate in the blood until they meet lipoprotein lipase (near AT), hydrolysis of TAG (FA taken up adipocytes, reesterified with glycerol-3-phosphate to form TAG) During well-fed state insulin from cells of the pancreas is in high concentration. These cells are very responsive to the influx of glucose and AA in the fed state. Rate of insulin/glucagon
Well-Fed State
Hepatic glycogenolysis Lipogenesis is curtailed Early fasting state Lactate, pyruvate and AA are diverted into formation glucose completing Cori cycle (conversion glucose to lactate, pyruvate in peripheral tissue, they are substrates for gluconeogenesis in liver) Alanine cycle, in which carbon and nitrogen return to the liver in the form of alanine (muscle metabolizes glucose to alanine, which is coming back to liver as a substrate for gluconeogenesis)
ing State
No fuels enters from the gut (duodenum) and little glycogen is left in the liver Tissues which require glucose are dependent on hepatic gluconeogenesis Cori and Alanine cycles play important role FAs can not be used for synthesis of glucose (acetyl- CoA can not be converted to glucose) Glycerol (by-product of lipolysis) becomes important substrate for gluconeogenesis AA, which are hydrolyzed in skeletal muscle (especially), supply most of the carbon atoms for net glucose synthesis mostly in the for of Ala and Gln
Most of Gln released from muscle is converted (oxidized) into alanine and NH 4 + by intestinal epithelium and being released into bloodstream (glutaminolysis) Gluconeogenesis in the liver fasting is closely connected with to urea cycle (ornithine, carbamoyl phosphate, citrulline). Most AAs can give up the amino nitrogen by transamination with 2-oxo glutarate. AT lipolysis is activated (low blood insulin), blood level of fatty acids raises and are used by peripheral tissues (heart, muscle, liver formation of glucose and ketone bodies)
FA oxidation in liver provide most of ATP needed for gluconeogenesis Acetyl~CoA is mostly converted to ketone bodies (small amount is oxidized completely) Ketone bodies and FA are preferred by many tissues over glucose; they can also suppress proteolysis and BCA oxidation in muscle Cooperation of tissues : liver synthesizes glucose, muscle and intestinal cells supply the substrate (alanine), and AT supplies the ATP (via FA oxidation in liver) needed for gluconeogenesis This cooperation is dependent on levels of hormones (insulin, glucagon, epinephrine) Reduction of triiodothyronine reduces daily basal energy requirements by 25%
Fasting State
After meal, fuel is again absorbed from gut Fat is metabolized like in well-fed state Glucose is poorly extracted by the liver, liver remains in the gluconeogenic mode for a few hours after refed. Hepatic gluconeogenesis provides glucose-6-phosphate for glycogenesis. Rather, glucose is catabolized in peripheral tissues to lactate which is converted in liver to glycogen (glucose paradox)and substrates from it are used by liver for gluconeogenesis and then glycogen. After the rate of gluconeogenesis declines, glycolysis becomes the predominant means of glucose disposal in the liver
Metabolic interrelationship of major tissues in the early refed state
Exercise Anaerobic exercise : sprinting or weight lifting (very little organ cooperation), muscle largely relies on its own stored glycogen and phosphocreatine. Aerobic exercise : long-distance running is metabolically more interesting. For moderate exercise, much of the energy is derived from glycolysis of muscle glycogen - content of it can be increased by exhaustive exercise that depletes glycogen, followed by rest and a high-carbohydrate diet. It is not enough glucose and glycogen for endurance running switching to fatty oxidation The respiratory quotient (the ratio of CO 2 exhaled to oxygen consumed) falls during running-this indicates the progressive switch from glycogen to fatty acid oxidation during the race.
Aerobic exercise
The liver is primarily responsible for the first two steps of ethanol catabolism Alcohol dehydrogenase Aldehyde dehydrogenase Liver disposes of NADH generated by this reaction only in mitochondrial electron transport chain ethanol generates too much NADH Some enzymes are inhibited by NADH (gluconeogenesis, - oxidation) and also TCA is inhibited The result is fasting hypoglycemia and accumulation of TAG Fatty liver, cirhosis Redundant acetate is metabolized in peripheral tissue Formation of acetaldehyde adducts with proteins in the body (control of abstinence)
Ethanol ingestion