Liver Biosynthetic Functions 2023 PDF

Royal College of Surgeons in Ireland Medical University of Bahrain Liver: biosynthetic functions A LEARNING OBJECTIVES 1. List the main functions of the liver 2. Explain how the liver metabolises proteins, carbohydrates and fats 3. Identify the main compounds synthesized by the liver 4. E...

Royal College of Surgeons in Ireland Medical University of Bahrain Liver: biosynthetic functions A LEARNING OBJECTIVES 1. List the main functions of the liver 2. Explain how the liver metabolises proteins, carbohydrates and fats 3. Identify the main compounds synthesized by the liver 4. Explain the synthesis of albumin and its functions in the body 5. Outline the haem biosynthetic pathway 6. Describe how defects in haem biosynthesis lead to the porphyrias Functions of the Liver  Carbohydrate metabolism  gluconeogenesis  glycogen synthesis and breakdown  Fat metabolism  fatty acid synthesis  cholesterol synthesis and excretion  lipoprotein synthesis  ketogenesis  bile acid synthesis  25-hydroxylation of vitamin D  Protein metabolism  synthesis of plasma proteins (including some coagulation factors but not immunoglobulins)  urea synthesis Synthetic role of liver Plasma proteins incl. albumin Glucose Gluconeogenesis (& glycogenolysis) Ketone bodies Cholesterol and trigylcerides Bile acids Glutamine and urea Nucleotide precursors purines and pyrimidines Haem Protein metabolism in liver Deamination and transamination of amino acids conversion of non-nitrogenous part to glucose or lipids Removal of ammonia from the body by synthesis of urea Ammonia very toxic - if not rapidly and efficiently removed causes central nervous system disease Synthesis of non-essential amino acids Synthesis of proteins hepatocytes responsible for synthesis of most plasma proteins Albumin synthesized exclusively by liver Clotting factors necessary for blood coagulation Protein synthesis Two categories of proteins: Liver tissue proteins Structural proteins Enzymes Exported proteins – Plasma proteins albumin α and β globins fibrinogen Carbohydrate metabolism in liver Maintenance of normal blood glucose levels – over both short (hours) and long (days to weeks) term Three important processes include:- – glycogenesis [making glycogen] excess post-prandial glucose is taken up by the liver and stored as glycogen – glycogenolysis [breaking down glycogen] when blood glucose levels decrease, glycogen is broken down and glucose is exported into blood for transport to other tissues – Gluconeogenesis [making new glucose] when hepatic glycogen reserves are exhausted, glucose is synthesised from amino acids and non- hexose carbohydrates Metabolic homeostasis The Cori cycle 180g glucose produced per day from glycogen or gluconeogenesis:- - absolutely necessary for use by the brain and RBC 36g of lactate returned to liver for gluconeogenesis – the Cori cycle Remainder of gluconeogenesis supported by:- degradation of 75g of protein in muscle Lippencott’s 10.2 production of 16g of glycerol from lipolysis in adipose tissue 160g of triglyceride used:- glycerol to gluconeogenesis 25% fatty acids converted to ketones, rest used directly by tissues Fat metabolism in liver oxidation of triglycerides to produce energy – breakdown of fatty acids and generation of ketone bodies - used as energy source in remote tissues most lipoproteins synthesized in liver major site for converting excess carbohydrates and proteins into fatty acids and triglyceride – exported and stored in adipose tissue synthesizes large quantities of cholesterol and phospholipids – Some packaged with lipoproteins and made available to rest of body – remainder excreted in bile as cholesterol or as bile acids The liver plays an important role in lipid metabolism Oxidation of fatty acids regulation of blood triglycerides synthesis of: VLDL VLDL LDL HDL Medical Physiology-Principles for Clinical Medicine. R. A. Rhoades and D. R. Bell haem porphyrin ring (protoporphyrin lX) with ferrous iron chelated in centre synthesised in:- Haem Iron Bone marrow Haemoglobulin Fe2+ Muscle Myoglobin Fe2+ Liver Cytochromes / Cytochrome P450 Fe2+  Fe3+ Catalase Fe3+ Haeme biosynthesis and the porphyrias Synthesis of Haem Glycine and succinyl CoA are mitochondrion precursors for the synthesis of δ-aminolevulinic acid (ALA) by δ- aminolevulinate synthase in the mitochondrion ALA synthase Pyridoxal phosphate prosthetic group Rate-limiting step in haeme biosynthesis Inducible enzyme Half-life 1-3 hours Synthesis of Haem – physiological control mitochondrion Hemin: when porphyrin production exceeds apo-protein production, haem accumulates and is converted to hemin (hematin) by oxidation of Fe2+ to Fe3+ Hemin inhibits ALA synthase – “end product inhibition” Free haem inhibits production of ALA synthase Many drugs induce cytochrome P450.This reduces intracellular haem concentration and induces ALA synthase Synthesis of haem ALA is exported to cytosol 2 molecules of ALA combined by ALA dehydrase to make cytosol porphobilinogen ALA dehydrase is sensitive to inhibition by lead (and other heavy metals) Hydroxymethylbilane synthase and Uroporphyrinogen III synthase make Uroporphyrinogen III Synthesis of Haem mitochondrion Further enzymes cytosol Ferrochelatase enhances incorporation of Fe2+ into Haem (mitochondrion) mitochondrion The Porphyrias Group of metabolic disorders caused by partial defects in one of the haem biosynthetic enzymes (A complete deficiency would be fatal) Acute Intermittent Porphyria Due to a defect in Hydroxymethylbilane synthase aka: (Porphobilinogen deaminase) (Uroporphyrinogen I synthase) – 50% reduction in enzyme activity – 90% of people this with genetic trait never present Clinical manifestations due to accumulation of:- ALA Porphobilinogen Acute Intermittent Porphyria Acute attacks precipitated by: Induction of cytochrome P450 synthesis (haem containing enzymes) – Enzyme inducing drugs barbiturates, phenytoin and ethanol – Induction depletes small pool of free unbound haem – De-repression of ALA synthase occurs – ALA and PBG, substrates for hydroxyl-methylbilane synthase accumulate in blood and CSF Treatment – Hemin (haematin) – derived from Haem Represses ALA synthase Porphyrias – cutaneous manifestations – Porphyrins – Porphyrinogens – nonenzymatically converted to porphyrin Porphyrins photoexcited by sun- light on skin causing cellular damage Defects in the pathway after hydroxymethylbilane synthase result in photosensitive porphyrias Haeme biosynthesis and the porphyrias