12-3-meziorganelove vztahy 1 Overview of nutrient metabolism? The organ relations 12-3-meziorganelove vztahy 2 First law of thermodynamics U = W + Q = work + heat Energy can not be created nor destroyed, it can only be changed from one form of energy to another. Transformation of energy in human body Chemical E of nutrient = work + heat E of nutrient = BM + physical activity + reserves + heat BM = basal methabolism reserves = adipose tissue, glycogene Income of E Cost of E Every work needs- ATP chemical: synthesis of proteins.. ... osmotical: transport of ions ... mechanical: muscle contraction ... Respiratory chain_Biochemistry- 10 3 Chemical E of nutrient heat NADH+H+ FADH2 proton gradient heat heat ATP 1 2 3 1 ....... metabolically dehydrogenation 2 ....... RCH = oxidation of reduced cofactors and reduction of O2 to H2O 3 ....... Aerobic phosphorylation ............. High energetic system Transformation of E – production of heat Respiratory chain_Biochemistry- 10 4 nutrient E (kJ/g) Thermogenesis Source of E/day Lipids 38 4 %  30 % SAFA 5 %, MUFA 20 %, PUFA 5 % CH + sugars 17 6 % 55 - 60 % Proteins 17 30 % 10 - 15 % Nutrients and E Respiratory chain_Biochemistry- 10 5 12-3-meziorganelove vztahy 6 Chemical energy nutrients and thermogenesis Nutrient Energy (kJ/g) Thermogenesis Fat 38 4 % Carbohydra tes 17 6 % Proteins 17 30 % Thermogenesis is the generation of heat (generally after energy expenditure) 3-5 hours after intake of nutrients. Expressed in % received power for a given nutrient. Thermogenesis is related to digestion, absorption, transport and metabolism of nutrients. 12-3-meziorganelove vztahy 7 Two ways to produce ATP in the cell 95% of the ATP formed aerobic phosphorylation (in the presence of O2): ADP + Pi + H+gradient energy  ATP 5 % of the ATP formed by substrate phosphorylation: ADP + macroergic-P*  ATP + second product * 1,3-bisphosphoglycerate (glycolysis) phosphoenolpyruvate (glycolysis) succinyl-CoA + Pi  succinylP, succinate (CC) 12-summary of metabolism 8 Basal metabolism (BM) Even in utter calm the body must expend some basic (basal) amount of energy to the activity of the CNS, heart, constancy of the internal environment, transport through membranes, biosynthesis etc. Estimated level of BM: 0,1 MJ/kg/day Man, 70 kg  BM = 0,1 . 70 = 7 MJ/day 12-3-meziorganelove vztahy 9 Basal metabolism depend on • gender (female about 10% less) • age (age decreases) • body temperature (a temperature increase of 1 °C BM is increased by about 12%) • ambient temperature - stay in a cold environment increases BM • thyroxine hormones, adrenalin - increase BM • prolonged fasting - BM decreases (slimming diets, anorexia) 12-3-meziorganelove vztahy 10 Recommended Nutrient nutrient % income of energy/day Carboh. Lipids Proteins 55 – 60 %  30 % 10-15 % SAFA  5 % MUFA  20 % * PUFA  5 % Essential FA: linoleic acid, α-linolenic Conditionally essence. FA: arachidonic Essential AA: Phe, Trp, Val, Leu, Ile, Met, Thr, Lys Conditionally essence. AA: His, Arg (childhood), Ala, Gln (Metab. Stress) * 67 % 12-3-meziorganelove vztahy 11 The supply of nutrients in the body (male, 70 kg) Nutrient Location weight (g) Energy (MJ) Glycogen Glycogen Glucose Lipids Proteins liver muscle ECT Adipose t muscle 70 120 20 15 000 6 000 1,2 2,0 0,3 570 102/3 = 34 • The largest reserve of energy forms fat The amount of total body fat is 10-30% ( men, women ) It is useful about ⅓ muscle mass without compromising the integrity of the organism Liver glycogen lasts about 24 hours Muscle glycogen - only for muscles (lack of glucose-6-phosphatase) 12-3-meziorganelove vztahy 12 Basic facts about metabolism • ATP is the immediate and universal source of chemical energy for cellular processes • ATP is generated as a result of oxidation of nutrients • nutrients  acetyl-CoA CC  RCh  ATP • The organism requires a constant level of ATP and glucose • Glucose is essential for brain and erythrocytes • Glucose is essential for the use of energy from fat = for the course of CC(Glc  pyruvate  oxalacetate  CC) • Glucose can not be synthesized from fats 13 Metabolic intermediates and their relationships + mixed- CO2 esencial pyruvate glucose acetyl-CoA irreversible irreversible Ketogenic AA CCGlucogenic AA FA glycerol TAG 12-3-meziorganelove vztahy 14 Interconversion of nutrients Conversion Comments Carbohydrates  lipids Easy and quick Lipids  glucose Not possible Pyruvatedehydrogenation is irreversible Amino acids  glucose Majority of AA is glucogenic Glucose  amino acids Pyruvate and intermediate of CC give carbon sceleton for AA synthesis Amino acids  lipids In case excess proteins in diet Lipids  amino acids Pyruvatedehydrogenation reaction is irreversible ketogenic + mixed AA are essential × × 12-3-meziorganelove vztahy 15 Metabolism in resorptive phase • After meal • Enough nutrients, it is not necessary to save • Chemical energy is stored in reserves • Hormonal regulation - Insulin 12-regulation 16 Carbohydrates in the resorptive phase (insulin) Glc intestine liver Glc glycogen Glc in blood lactate ery CNSCO2 TAG NADPH Adipose tissue glycerol-P TAG muscle glycogen CO2 GLUT4 dependent on insulite CO2 Gln CO2 CO2 TEST 12-regulation 17 Metabolism of glucose in the liver (after meal) • glucose at this stage is rarely used as metabolic fuel for the liver • Insulin increases glycolysis (induces the synthesis of glucokinase) • Part of glucose is converted to hepatic glycogen • In excess glucose, there are synthesize TAG as VLDL  adipose tissue –obesity • part of glucose in the blood passes through the liver • a small proportion of glucose provides specialized products (pentose cycle NADPH and ribose, galactose, glucuronate) 12-regulation 18 Extrahepatic glucose utilization • a single power source for erythrocytes (anaerobic glycolysis) • prominent energy source for the CNS (aerobic glycolysis) • main source of energy for muscles at rest (aerobic glycolysis), muscle glycogen synthesis (limited capacity) • power source, glycerol-3-P and NADPH + H + for TAG in adipose tissue Glc   glyceraldehyd-3-P + dihydroxyaceton-P glycerol-3-P 12-regulation 19 Lipids and proteins in the resorption phase (insulin) AA intestine liver Glc TAG Adipose tissue FA + glycerol-P TAG muscle CO2 AA TAG VLDL FA myovard FA chylomicrons LPL LPL LPL proteins Gln FA BCAA NH3 proteins Blood plasma TEST 12-regulation 20 Lipids in resorptive phase • exogenous TAG are hydrolyzed in the intestine, in enterocytes are resynthesized and built into chylomicrons • endogenous TAG formed in the liver as VLDL • lipoproteins are directed mainly in adipose tissue (raised in adipose tissue LPL) • FA secondary uses are also in muscle (primary glucose) and other tissues (myocardium, kidneys ad.) • FA  acetyl-CoA  CC  CO2 + energy 12-regulation 21 Amino acids in the resorptive phase • AA are partially metabolized in enterocytes (Gln) • part is utilized by the liver to synthesize proteins • from excess amino acids are formed FA and TAG • Val, Leu, Ile (= BCAA) are not utilized in the liver (missing aminotransferase) utilized by the muscles, CNS 12-regulation 22 Liver • increased phosphorylation of glucose  Glc-6-P (glukokinase) • Glc-6-P  CO2 + energy (exceptionally metabolic fuel for the liver) •Glc-6-P  glycogen (supply of glucose to other organs) • Glc-6-P   NADPH+H+ (pentos. cycle)   MK   TAG  VLDL • AK  liver proteins + blood plasma proteins • AA in excess carbon skeleton (oxidation) + ammonia   urea Tuková tkáň • increased glucose influx (GLUT4 / insulin) • increased glycolysis energy + glycerol-3-P (for lipogenesis) • increased pentose cycle  MK (synthesis of FA de novo is not important) • influx FA z CM + VLDL (LPL)  TAG (llipogenesis) Adipose tissue • increased glucose influx (GLUT4 / insulin) • glucose  CO2 + energy • increased glycogen synthesis (need for muscle) • income of AA (esp. BCAA)  protein synthesis (+ AA oxidation) Brain • glucose  CO2 + energy Kidneys • glucose / FA / glutamine  CO2 + energy !Summary of reactions in the resorptive phase (insulin) 12-regulation 23 Insulin • After a meal, insulin is released from pancreatic β-cells • Decreases in blood glucose concentration by • A) increases the transport of glucose into muscle and fat. tissue • B) stimulates the synthesis of glycogen (liver, muscle) • C) inhibits glycogenolysis and gluconeogenesis • D) supports glycolysis in tissues (liver, muscles ...) • At the same time promotes the synthesis of TAG (tt, liver) and proteins (non-specifically) 12-regulation 24 Inzulin is anabolic hormon Fatty Acids TAG glucose glycogenCO2 glycolysis Amino Acids proteins Supports the construction of storage compounds and cellular glucose utilization Insulin induces the synthesis of key enzymes of glycolysis (glucokinase, phosphofructokinase, pyruvate kinase), and glycogenesis 12-regulation 25 Post resorptive phase • Fasting (first feelings of hunger) • About 10-12 hours after the last meal (before breakfast) • Hormonal regulation – glucagon 12-regulation 26 Carbohydrates and proteins in Post resorptive phase (glucagon) intestine liver Glc glycogen Glc in blood lactate (100%) ery CNSCO2 muscle glycogen 90% gluconeogenesis 10% glukoneogenesis kidney lactate CO2 proteolysis Ala, Gln phosphoro lysis Metabolis fuel for some tissues Gln  CO2 TEST 12-regulation 27 Glucose in post resorptive phase (glucagon) glucose in blood is controlled by two processes: (1) hepatic glycogenolysis (phosphorolysis) (Glc)n + Pi  (Glc)n-1 + Glc-1-P Glc-6-P  free Glc (2) The hepatic gluconeogenesis from non-sugar precursors alanine, more glucogenic AK, glycerol, lactate phosphorylase is activated by glucagon and adrenalin glucagon induces synthesis of three key enzymes: fosfoenolpyruvátkarboxykinasa (PEPCK) fructose-1,6-bisfosfatasa glucose-6-phosphatase 12-regulation 28 Asp Ser, Gly, Thr, Ala, Cys, Trp Most (14) amino acids are glucogenic oxalacetate fumarate succinyl-CoA 2-oxoglutarate CC acetyl-CoA Phe, Tyr Ile, Val, Met, Thr Arg, Glu, Gln, His, Pro Asp, Asn glucose acetoacetate pyruvate Ile, Leu, Lys, Thr Leu, Lys, Phe, Trp, Tyr 12-regulation 29 Lipids in the post resorptive phase (glucagon) intestine liver Acetyl-CoA Ketone bodies Ketone bodies in blood CNS CO2 muscle FA CO2 Adipose tissue FA + glycerol TAG FA-albumine myocard kidneyHSL CO2 Gln  CO2 TEST 12-regulation 30 Lipids in the post resorptive phase • In adipose tissue lipolysis occurs (hormone sensitive lipase) • FA are transported in the ECT, in relation to the albumin • FA are an energy source for the liver, muscles and myocardium • Ketone bodies are used in the muscles and partly in the CNS 12-regulation 31 Glucagon is antagonist of insuline • Second messenger cAMP • Promotes degradation of storage substances: glycogen (liver), TAG (a.t.) and proteins (liver) • Promotes gluconeogenesis from lactate and AA • It inhibits glycogen synthesis, and protein TAG • acts on liver and fat. tissue (not muscle) 12-regulation 32 Glucagon is the antagonist of insulin (Ketogenic hormone) FA TAG glucose glycogen CO2 AA Ketone bodies Glucagon induces synthesis of three key enzymes of gluconeogenesis: PEPKC, Fru-1,6-bisfosfatasu, glc-6-phosphatase 12-regulation 33 ketone bodies No electrolyteanionanion Na+ Cl- HCO3 - OA K+ Ketone bodies are three water-soluble molecules that are produced by the liver from fatty acids during periods of low food intake (fasting) or carbohydrate restriction for cells of the body to use as energy instead of glucose. Two of the three are used as a source of energy in the heart and brain while the third (acetone) is a degradation breakdown product of acetoacetic acid. acetone, acetoacetic acid, and beta- hydroxybut yric acid H3C C CH3 O H3C CH CH2 C O OH OH H3C C CH2 O C O O H - CO2 - 2H + 2H b-hydroxybutyric acid Acetoacetic acid aceton TEST 12-regulation 34 Ketone bodies as source of energy acetoacetate acetoacetyl-CoA succinyl-CoA: acetoacetate-CoA transferasa H3C C CH2 O COOH sukcinyl-CoA sukcinát H3C C CH2 O C SCoA O S H CoA C SCoA O H3C2 CC Energy TEST 12-regulation 35 A summary reactions in post resorptive phase (glucagon) Liver • increased glycogenolysis • gluconeogenesis (from Ala, AA, lactate/pyruvate, glycerol) • increased β-oxidation FA  acetyl-CoA   ketone bodies  export KB Adipose tissue • increased lipolysis (HSL / glukagon, adrenalin)  FA + glycerol • increased export FA to blood Muscle • FA (from AT) + ketonebodies (from liver)  CO2 + energy • long fasting – FA only oxidated • proteolysis  AA (mainly Ala, Gln – for liver gluconeogenesis) / kortisol Brain • glucose  CO2 + energy • ketone bodies  CO2 + energy (long fasting) kidney • glucose / FA / ketone bodies / glutamin  CO2 + energy • gluconeogenesis (for kidney and others) • compensation of keto acidosis : Gln/Glu  NH3 + H+  NH4 + (excretion to urine) !glucosa-6-phosphatase 12-regulation 36 Carbohydrate metabolic turnover during starvation (g/d) glycogen glukoneogenesis liver AK Glycerol 16 144 CNS 36 Ery Lactate 36 Glc 180 gluconeogenesis liver AK Glycerol 15 44 CNS 36 Ery lactate 50 Glc 80 Short-term Long-term 75 20 Proteiny Proteiny 12-regulation 37 Carbohydrate metabolic turnover during starvation • Gluconeogenesis in the liver gradually decreases • muscle proteolysis gradually decreases • Substrates for gluconeogenesis are unchanged (lactate, AA, glycerol) • CNS decreases glucose utilization • Proportion Ery Glc consumption remains constant (36 g / d), which during prolonged fasting can be up to 45% of production Glc 12-regulation 38 Lipid metabolic turnover during starvation (g/d) gluconeogenesis liver glycerol Ketone bodies 60 Short-term Long-term TAG 160 MK 40 FA 160 FA 120 Muscle, myocard, kidney glukoneogenesis liver glycerol Ketone bodies 57 TAG 150 MK 38 FA 150 FA 112 Muscle, myocard, kidney 10 moč CNS 47 x 12-regulation 39 Lipid metabolic turnover during starvation • The extent of lipolysis in adipose tissue remains roughly the same • Production of ketone bodies is also roughly equal (acidosis) • Muscles cease to use ketone bodies • The brain gradually adapts to ketone bodies 12-regulation 40 The main priorities of the body during starvation • Saving of glucose (utilization of ketone bodies in the brain) Saving of proteins (ketones limit of gluconeogenesis AA) 12-regulation 41 Metabolism during stress - catecholamines • Noradrenaline, adrenaline - released from the adrenal medulla • It operates via adrenergic receptors • β-receptors - cAMP - muscles, fat. tissue • α1-receptors - IP3 DAG + (Ca2 +) - liver • Effect of very quick - seconds • Primarily stimulate: • Glycogenolysis in the liver ( increase in blood Glc) • Glycogenolysis and glycolysis in muscle • Lipolysis in adipose tissue • The power supply for the muscles that must react quickly to the situation (fight, flight) 12-regulation 42 Organism in a state of emergency (fight or flight) liver FA muscle adrenalin TAG glycogen glycogenGlc Glc Adip.tissue ATP 12-regulation 43 Glucocorticoids are released in chronic stress • Cortisol - potentiates the effect of adrenaline • Prepares the body for the effect of adrenaline • Affects the expression of genes - the effect of slow – hour to days • stimulates the HSL synthesis in fat. tissue – instress, there is enough available enzyme cleavage of stored fats • supports muscle proteolysis - substrates for gluconeogenesis • Induces the synthesis of PEPCK (gluconeogenesis) and glycogen synthase