Liver Biosynthetic Functions PDF

Liver Biosynthetic Functions GIHEP, Yr2 Medicine Dr. Stephen Keely  Learning Outcomes By the end of this lecture you should be able to: 1. List the main functions of the liver 2. Explain how the liver metabolises proteins, carbohydrates and fats 3. Identify the main compounds synt...

Liver Biosynthetic Functions GIHEP, Yr2 Medicine Dr. Stephen Keely  Learning Outcomes By the end of this lecture you should be able to: 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 METABOLISM Carbohydrate Metabolism - Glycogen synthesis (glycogenesis) - Glycogen breakdown (glycogenolysis) SYNTHESIS - Gluconeogenesis EXCRETION & Nutrients (glucose, Fatty acid metabolism DETOXIFICATION TGs, AAs) Plasma proteins Protein metabolism Bilirubin Haem NH3 (Urea Cycle) Coagulation factors Cholesterol and Urea steroid hormones Bile acids Drugs Toxins Functions of the liver: Metabolism  Carbohydrate Metabolism - Dietary carbohydrates are broken down into simple sugars (mostly glucose) and used as energy - Important function of the liver is to maintain blood concentrations of glucose - Dietary glucose is taken up by the liver and stored as glycogen (glycogenesis). - When blood glucose declines glycogen is broken down and glucose is released (glycogenolysis) - When hepatic glycogen is depleted (ie. in the fasting state) the liver synthesises glucose from non-carbohydrate sources (glycerol, lactate, AAs) (gluconeogenesis). - Controlled by insulin (storage), cathecholamines & glucagon (mobilisation)  Lipid Metabolism The liver: - oxidizes triglycerides to produce energy. - Converts FAs to ketone bodies - Exports acetoacetate to other tissues where it can be picked up and metabolized. - Converts excess carbohydrates and proteins into fatty acids and triglyceride - Synthesizes cholesterol and phospholipids. - Lipoproteins are synthesized in the liver (VLDLs). - used to export TGs, cholesterol and phospholipids to other tissues  Protein Metabolism Most important aspects of protein metabolism in the liver are: - Deamination and transamination of amino acids, followed by conversion to glucose or lipids (for entering the TCA cycle) - Removal of ammonia from the body by synthesis of urea. - Ammonia is very toxic and can cause encephalopathy. - Synthesis of non-essential amino acids (e.g., glutamine) - Synthesis of most of the plasma proteins (e.g., albumin, gamma globulins) - Synthesizes many of the clotting factors necessary for blood coagulation (e.g., fibrinogen) Vitamin metabolism in the liver Vitamin D/choleocalciferol (precursor form; SKIN) 25-hydroxy-Vitamin D (circulating form; LIVER) 1,25-dihydroxy-Vitamin D (active form; KIDNEY)  Biosynthetic Products of the Liver Nutrients - Triglycerides, cholesterol, phospholipids, lipoproteins - Glycogen, glucose - Non-essential amino acids Others - Plasma Proteins (e.g., albumin, globulins) - Haem - Clotting factors (Fibrinogen) - Bile Acids - Nucleotide precursors - Urea  Plasma proteins synthesised by the liver Many proteins are synthesized in the liver and secreted into the blood Carrier proteins– carry many fat soluble nutrients, hormones, drugs, etc. (e.g., albumin, globulins) Clotting/Anticlotting Factors – regulate blood coagulation (e.g., fibronectin, components of the complement cascade) Hormones – regulate various aspects of metabolism and growth (e.g., fibroblast growth factor, insulin like growth factor) Apolipoproteins – enable transport of lipids in the blood  Plasma proteins synthesised by the liver Albumin Synthesised only in hepatic cells www.pdb.org Most abundant protein in the serum – approximately 15 g/d in healthy adult Is negatively charged – Attracts positively charged molecules and ions Functions i) Transports many substances in the blood - has binding sites for many endogenous and exogenous compounds (eg. bilirubin, fatty acids, metals, ions, hormones, exogenous drugs) ii) Regulates fluid distribution between the blood and body tissues - Provides 75-80% of the oncotic pressure in the blood  Control of blood volume by albumin Oncotic pressure (colloid osmotic-pressure) = type of osmotic pressure due to plasma proteins, most notably albumin, in the blood Amount of fluid in the blood vessels is largely determined by 2 opposing forces: - Hydrostatic pressure – pushes fluid into the interstitium. - increases volume of interstitial fluid - Oncotic pressure – pulls fluid from interstitium into the blood by osmosis. - increases volume of interstitial fluid  Control of blood volume by albumin Hypoalbuminemia - Reduced albumin in the blood due to either - impaired synthesis in the liver (e.g., liver cirrhosis) - or increased renal excretion due chronic kidney disease(e.g., nephrotic syndrome ) - Results in decreased plasma oncotic pressure - Blood volume decreases & interstitial fluid increases - leads to fluid-induced swelling of the extremities (edema) - build-up of fluid in the abdomen known as ascites  Albumin synthesis Initially synthesized as a preproprotein = albumin & 24 amino acid (AA) extension at N terminal end Processed in endoplasmic reticulum → 18 AA cleaved off to yield proalbumin Proalbumin exported to Golgi apparatus → 6 AA extension removed to yield albumin Secreted immediately (not stored in liver) Normally, ~ 14g synthesised/day -rate of synthesis is regulated by colloid pressure, inflammatory mediators & cortisol  Distribution of albumin – Albumin is secreted from the liver either by: entering the lymphatic system and then the blood via the thoracic ducts or passing directly from hepatocytes into liver sinusoids – 40% remains in the blood and 60% enters the interstitium – In the intravascular space Albumin has a T1/2 ~17 days degradation rate about 4% per day (mechanism unknown ) – Levels of albumin can be measured in the blood Hyeralbuminemia - dehydration & severe diarrhea Hypoalbuminemia - kidney disease, liver disease, inflammation or infections – Albumin not normally excreted in urine but if it is, it is a likely sign of kidney disease  Globulins – 2nd most abundant plasma protein – 3 types - a, b, g globulins – Not only made in the liver but also in immune cells – Perform a variety of functions Transport of other substances Enzymatic activity Clotting factors Immune function (g globulins, IgA, IgM) Exert oncotic pressure – Altered plasma levels can be indicative of disease Decreased: Increased: Genetic disorders Inflammation & infection (eg. 1-antitrypsin deficiency) Autoimmune disease Malnutrition Cancer  Haem synthesis by the liver What is haem? A chemical in which iron is chelated in the centre of a heterocyclic organic ring called a Porphyrin ring (protoporphyrin lX) - Synthesised in liver, muscle, and bone marrow - Red organic pigment to which oxygen binds Functions Heme is an essential cofactor for hemoproteins - involved in numerous processes – oxygen transport (hemoglobin), oxygen storage (myoglobin), oxygen metabolism (oxidases), antioxidation (peroxidases, catalases) electron transport (cytochromes)  1. Synthesis is initiated in the mitochondria Synthesis of haem by liver cells where the enzyme, ALA synthase acts on glycine and succinyl Co-A to give Aminolevulinic Acid (ALA) 2. ALA is transported into the cytoplasm where it is acted on by ALA dehydratase to give porphobilinogen (PBG) 3. PBG is acted on by PBG deaminase to give hydroxymethylbilane 4. Hydroxymethylbilane is converted to Uroporphyrinogen (UPO) and then Coproporphyrinogen by UPG decarboxylase 5. Coproporphyrinogen re-enters the mitochondria where it is converted in protoporyrin 6. Protoporphyrin is chelated to iron by https://www.youtube.com/watch?v=IvdaQd9IK4s ferrochelatase to give Haem.  Synthesis of haem by liver cells 1. Synthesis is initiated in the mitochondria where the enzyme, ALA synthase acts on glycine and succinyl Co-A to give Aminolevulinic Acid (ALA) 2. ALA is transported into the cytoplasm where 2 moelcules are combined by ALA dehydratase to give porphobilinogen (PBG) 3. 4 molecules of PBG are acted on by PBG deaminase to give hydroxymethylbilane 4. Hydroxymethylbilane is converted to Uroporphyrinogen (UPG) by UPG Synthase and then Coproporphyrinogen by UPG decarboxylase 5. Coproporphyrinogen re-enters the mitochondria where it is converted in protoporphyrin 6. Protoporphyrin is chelated to iron by ferrochelatase to give Haem.  Regulation of haem synthesis - Haem levels are the most important factor regulating the rate of Haem synthesis. - Haem inhibits ALA synthase expression and activity in hepatocytes. - Haem also stimulates globin synthesis (for haemoglobin) helping to keep levels of free haem low The balance between inhibition of ALA synthase and stimulation of globin synthesis is key to homeostatic regulation of haemoglobin production. https://www.youtube.com/watch?v=IvdaQd9IK4s Defects in haem synthesis - Lead Poisoning - The Porphyrias - Acute intermittent porphyria (AIP) - Porphyria Cutanea Tarda (PCT) Metabolic consequences of impaired enzyme activity Alternate product Enzyme Substrate X Product Accumulation of substrate Deficiency of product Diversion to alternate product?  Lead Poisoning Pb2+ - Occurs both in adults and children - Exposure to lead in paint, dust in old buildings, batteries, auto industry etc. - Symptoms: Anemia, constipation, abdominal pain, irritability, seizures, coma. - Mechanism: Inhibition of ALA dehydratase and ferrochelatase - Haem is not produced (microcytic anemia) - Increased ALA levels are neurotoxic - Therapy: - Remove the source - Chelation therapy (e.g., succimer, EDTA)  Porphyrias - Group of liver disorders resulting in accumulation of porphyrins in the body - Usually hereditary - Due to mutations in enzymes that synthesise haem - Characterized by excretion of porphyrins in urine - urine becomes red/purple in colour - Causes: decreased haem production and a build-up of heme pathway intermediates (ie., porphyrins) - Often triggered by external factors - (e.g., medications, stress, hormonal changes, fasting) - Symptoms: abdominal pain, vomiting, confusion, fever, constipation, ↑ BP, seizures. - Several subtypes depending on deficient enzyme Porphyrins = macrocyclic - e.g., Acute intermittent porphyria (AIP) structures consisting of four pyrrole rings - Porphyria Cutanea Tarda (PCT)  Acute intermittent porphyria (AIP) Due to a defect in porphobilinogen deaminase (aka, uroporphyrinogen synthase I) Attacks are triggered by several factors X – e.g., drugs which induce expression of X cytochrome p450 enzymes (haemoproteins) (e.g., barbiturates, progesten) – Haem synthesis pathway is switched on but is defective. Manifestations are mostly due to accumulation of ALA and PBG (not so much decreased haem) Reduced haem leads to loss of negative feedback, thereby further increasing ALA and PBG Symptoms: Seizures, Diagnosis: Treatment: Use haematin psychosis, severe Measure urinary - synthetic form of haem abdominal pain, nausea ALA and PBG -restores inhibition of ALA & vomiting, coma. levels.  Porphyria Cutanea Tarda (PCT) Due to a defect in uropoprhorinigen decarboxylase Causes a build-up of uroporphorinigen and X decreased heme – UPO accumulates close to the skin – UPO is photosensitive and becomes X oxidised by sunlight – Oxidised UPO causes cell damage, inflammation, blistering and discolouration of the skin. Symptoms: Treatment: Avoid excess sunlight, Swelling, itching, Diagnosis: alcohol, and iron supplements. Anti- blistering of the Measure malarials (eg., chloroquine) can be skin upon urinary UPO. used exposure to sun - bind UPO and promote urinary excretion