* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Regulation of Organic Metabolism, Growth, and
Survey
Document related concepts
Oligonucleotide synthesis wikipedia , lookup
Clinical neurochemistry wikipedia , lookup
Deoxyribozyme wikipedia , lookup
Two-hybrid screening wikipedia , lookup
Amino acid synthesis wikipedia , lookup
Biosynthesis wikipedia , lookup
Proteolysis wikipedia , lookup
G protein–coupled receptor wikipedia , lookup
Lipid signaling wikipedia , lookup
Paracrine signalling wikipedia , lookup
Fatty acid metabolism wikipedia , lookup
Biochemistry wikipedia , lookup
Signal transduction wikipedia , lookup
Artificial gene synthesis wikipedia , lookup
Transcript
Metabolism The goal of this lectures is to discuss basic physiology associated with the control of metabolism, such as the neuroendocrine control of pre- and post- absorptive states. The sections for this lecture are: 22 Introduction Neuroendocrine control of metabolism Insulin and Glucagon Growth hormone(GH) and growth factors (IGF) Thyroid hormones (tri / tetra iodotyronin,T3 and T4) Catecholamines (Cas, Epi and Norepinephrine) Glucocorticoids (Cortisol in humans) Major metabolic pathways of the absorptive state Major metabolic pathways of Life is a series of chemical reactions occurring in compartmentalized environments. The main purpose of life is to keep itself alive Physiology, the study of how life works, is based on the simultaneous occurrence of the following three concepts: levels of organization structure / function relationship homeostatic regulation the post - absorptive state Introduction central integration center afferent receptor S E the endocrine system plays a predominant role in the neuroendocrine control of metabolism efferent effector negative feedback signal 1 Introduction FUEL METABOLISM IN ANABOLIC / CATABOLIC PHASES State Hormones Fuel Process Source anabolism Insulin diet Glycogen synthesis Triglyceride synthesis Protein synthesis storage depots Glycogenolysis Lipolysis Proteolysis Ketogenesis Glucagon catabolism Insulin Glucagon Introduction 2 Introduction glycogen phosphorilase glycogen glycogen synthetase G-1-P G-6-Pase glucose hexokinase glucose G-6-P F-6-P F-1,6-diPase PFK F - 1,6 -diP transaminases insulin glucagon epinephrin cortisol triose amino acids pyruvate proteins Krebs cycle acetyl CoA fats Introduction Absortive State 3 Introduction Post - Absortive State Introduction 4 Introduction Introduction 5 Introduction The main endocrine systems involved in the neuroendocrine control of metabolism are Introduction 6 Insulin Insulin • 51 aa, 2 chains, 3 disulfide bonds, C-peptide • stimulates anabolism and favors energy storage • increases glycogen storage and inhibits both glycogen breakdown and gluconeogenesis • increases fatty acid synthesis and decreases lipolysis and ketogenesis • stimulates transport of glucose and of some aminoacids into striated muscle / adipose tissue • increases protein synthesis in liver, muscle, adipose • like growth factors, has a growth promoting effect 7 Insulin Insulin Tyr-P of docking protein IRS - 1 Cys rich hydrophobic aa kinase insulin NH2 ECF memb ICF COOH SH2domain mediated complex formation Ser - Thr kinase cascade DNA synthesis and gene transcription SOS ras raf MEKK MAPK phosphatidyl inositol -3 -P stimulation of glucose transport p90rsk PP1G glycogen synthase 8 Insulin Cys rich hydrophobic aa kinase insulin NH2 ECF memb ICF COOH Insulin CHIEF ACTIONS OF INSULIN ON METABOLIC PATHWAYS glycogenolysis gluconeogenesis phosphorylase (glucose-dependent de-P) PEPCK (transcriptional regulation) FDPase-2 (enzyme dephosphorylation) ketogenesis substrate (alanine) delivery from muscle glycogen synthesis fatty acid synthesis substrate (FFA) delivery from fat glycogen synthase (enzyme de-P) acetyl CoA carboxylase (transcription) fatty acid synthase Muscle proteolysis protein synthesis glucose uptake glycogen synthesis multiple mechanisms activity at multiple steps recruit Glut-4 to cell surface glucose uptake glycogen synthase (enzyme de-P) Fat lipolysis hormone sensitive lipase (enzyme de-P) triglyceride synthesis delivery of tryglyceride from liver lipoprotein lipase Liver 9 Insulin Insulin 10 Insulin Insulin 11 Anti insulin controls Glucagon 12 Glucagon • the main counterregulator to insulin together with catecholamines (epinephrine) & cortisol • 29 aa, member of a family of related peptides that includes VIP, GIP, and secretin • determines glycemia in postabsorptive state through glycogenolysis and gluconeogenesis • glucose, insulin and SS inhibit its release • aa, exercise and CAs stimulate its release • gene expression is restricted to cells in islet and is negatively regulated by insulin • glycentin, GI specific proteolytic processing Glucagon glucagon R cell membrane Gs AC phosphodiesterase ATP ----------> cAMP -----------------------------------> 5’AMP inactive PKA ----------> active PKA inactive PKb <----------> active PKb glycogen phosphorilase b <----------> glycogen phosphorilase b glycogen + Pi ----------> glucose - 1 - P cell membrane T blood glucose 13 Glucagon CHIEF ACTIONS OF GLUCAGON ON METABOLIC PATHWAYS LIVER glycogenolysis glycogen phosphorylase (cAMP-dep-P) glycogenesis glycogen synthase (phosphorylation) F - 1,6 - diPase (phosphorylation) gluconeogenesis pyruvate kinase (phosphorylation) glycolysis substrate delivery, releasing inhibition of carnitine palmytoil transferase, allowing mitochondrial transfer and FA oxidation ketogenesis Glucagon Glucagon and Glucose Metabolism Glucagon and Fat Metabolism Glucagon and Protein Metabolism 14 Glucagon Insulin / Glucagon 15 Growth Hormone Growth Hormone • • • • • • • • lowers blood aminoacid concentrations lowers blood urea nitrogen. Positive N balance increases DNA, RNA, and protein synthesis elevates glycemia by decreasing CH utilization and the sensitivity to the insulinhypoglycemic effect elevates fat oxidation. Lowers respiratory quotient induces growth in general mostly through IGFs stimulates growth and calcification of cartilage (IGFI) GH abuse causes diabetes mellitus by exhaustion of ß-cells overstimulated by high glycemia (meta- hypophyseal diabetes). Impaired glucose tolerance in acromegaly might be related to this interaction 16 Growth Hormone chemical stimuli hypothalamus ultra short loop GHRH SS negative feed-back anterior pituitary stress centers sleep centers long loop negative feed-back GH liver short loop negative feed-back GHRH-BP GH - BP & DHT somatomedins or IGF tissues Growth Hormone • the GHRH peptide: • G - protein linked receptor • AC/cAMP, PLC / IP, PLA/ PGE • sexual dimorphism (DHT) • have receptors for SS • the SS peptide: • G - protein linked receptor • Gi, AC, open K channels, hyperpolarization, lower Ca influx to cell seven transmembrane domain receptor NH 2 ECF plasma memb G ICF COOH GDP enzyme GTP channel 17 Growth Hormone MUSCLE LIVER prot synthesis RNA synthesis gluconeogenesis aa uptake prot synthesis glucose uptake increased muscle mass ADIPOSE glucose uptake lipolysis SM production IGF - I chondrocytes of bone collagen synthesis protein synthesis cell proliferation increased linear growth decreased adiposity IGF - II many organs and tissues protein synthesis RNA synthesis DNA synthesis cell size and number increased tissue growth and increased organ size Growth Hormone • GH receptors do not have a kinase • Dimerization, if GH excess inhibition • Ligand binding results in rapid phosphorylation of cell proteins on Tyr • Janus (JAK) kinases are cytoplasmic tyrosine kinases which physically associate with the box 1 - box 2 domains of the ligand bound receptor leading to auto - phosphorylation on Tyr residues and phosphorylation of transcription factors called “signal transducers and activators of trans-cription” or in short “STATS” • Most GH effects are mediated by IGFs kinase Cys residues hydrophobic aa GH JAK2 DNA STAT 18 Growth Factors Cys residues • GFs have Tyr-K except TGFß which phosphorilates Ser / Thr residues • receptor dimerization • amplification through multiple kinases & stats (signal transducers and activators of transcription) • long-term effects of GFs are dependent on shifts in gene expression kinase hydrophobic aa Cys rich GFs-BP as local storage also ? IGF II EGF PDGF NH2 insulin IGF I COOH JAK2 STAT GH Prl cytokines Thyroid Hormones 19 Thyroid Hormones Major Functions of the Thyroid Hormones Thyroid Hormones 20 Thyroid Hormones TRH and TSH NH 2 ECF plasma membrane G ICF GDP COOH enzyme GTP channel Thyroid Hormones T3 / T4 21 Thyroid Hormones TSH R AC (tyrosin) T cAMP MIT pump (tyronine) DIT I- 2 I I- 2 T3 I T4 TBG TBPA albumin T3 T4 protease lysosome colloid droplet t h y r o g l o b u l i n Thyroid Hormones T3 / T4 Na / K ATPase 22 Thyroid Hormones DNA binding region NH 2 1 Hormone binding region COOH Structure of nuclear hormone receptors 563 estrogen 1 946 1 777 1 glucocorticoid 917 thyroid hormone androgen 427 Vitamin D 408 1 progesterone 1 Thyroid Hormones empty binding site inactive co-repressor COOH T3R T3R HRE TFIIB TATA box RNAPol II DNA co-repressor COOH T3 active T3R T3R HRE TFIIB TATA box RNAPol II DNA 23 Thyroid Hormones 500 500 T3 Pituitary extract + T4 body weight (g) increased metabolism (ml O2/100g/h) pituitary extract 300 T4 300 normal Tx + T4 100 thyoidectomy, Tx 100 0 100 200 dose of thyroid hormone 0 100 200 time in days Catecholamines 24 Catecholamines Catecholamines 25 Catecholamines Catecholamines • Epi, NE, Ach, DA, glucagon seven transmembrane • Gs (ß1,ß2), Gi (2), Gq (1) domain receptor • adrenoreceptors are upregulated in NH the absence of stimulation and 2 ECF downregulated under continuous stimulation (eg. denervation plasma supersensitivity vs continuous membrane isoproterenol) G • adrenoreceptor responses to Cas ICF are affected by gonadal steroids GDP COOH (eg.uterine contraction due to CAs in E2 vs P4 mileau) enzyme • cortisol is permissive for cAMP GTP metabolic and pressor effects channel • T3 & sympathoadrenal activity 26 Catecholamines • under stress blood glucose should be elevated for energy production by brain, heart, skeletal muscle • Epi stimulates hepatic glycogenolysis (ß receptor) • muscle glycogen, lactic acid, liver (gluconeogenesis) • Cas inhibit insulin / stimulate glucagon (ß receptor) • hypoglycemia stimulates adrenal Epi secretion by a CNS glucoreceptor (blocked by anesthetic in hypoth) • Epi stimulates lipolysis by + HS-lipase and TG-lipase • FFA used as energy source (glucose-sparing action) • Epi decreases muscle proteolysis and aa release which might be of physiological importance to its short-term response associated with stress (ß recept) Glucocorticoids 27 Glucocorticoids Glucocorticoids Effect of Cortisol on Organic Metabolism 28 Glucocorticoids • increases gluconeogenesis by a genomic mechanism • inhibits glucose transport thus decreases its utilization • reduces aa use for protein formation except in the liver • increases FA / glycerol mobilization from adipose depot Glucocorticoids Zn fingers are binding regions of transcription factor proteins which attach to the promotor segment of DNA G H G R R HSP 90 HSP 90 Zn G H G H R R Zn Zn HRE HSP 90 TATA box RNA Pol II DNA HSP 90 29 Glucocorticoids gluconeogenesis and glucocorticoids • increase synthesis of gluconeogenic enzymes within hepatocytes (anabolic) • actions on skeletal muscle and adipose are catabolic (block glucose uptake, stimulate proteolysis, lipolysis, and promote FFA and glycerol mobilization) • glucose produced is either stored as glycogen or released into the blood • excessive secretion is antagonistic to insulin and promotes diabetes mellitus, an effect that is amplified since they reduce the affinity of certain cells for insulin, further aggravating the diabetes ZG ZF ZR Metabolism 30 Absorptive State Absorptive State 31 Postabsorptive State Postabsorptive State 32