Cellular Architecture and Physiology of the Liver

1. Cellular Architecture and Physiology of the Liver By: Jessica Thorpe, ShraddhaPanarker, Michael Perron, UsmanIqbal PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. Basic structure of the liver • Largest exocrine gland • Made of repeating units of hepatic lobules • Lobule vasculature consists of: • Central vein (located internally at center of the lobule) • Portal triad (portal vein, hepatic artery, bile duct) • Portal triad located at the peripheral corners of the lobule • Functional unit can also be observed as acini • Refers to three zone locations relative to afferent blood flow

3. Blood Flow • Hepatic portal system (mesenteric veins, gastrosplenic veins and hepatic portal vein) • Afferent blood flow via portal triad (portal vein and hepatic artery) • Portal vein contains nutrient-loaded blood from the GI tract • Hepatic artery contains oxygenated blood from heart • Efferent blood flow via central vein • Goes to the heart via vena cava • Peripheral to centre flow of blood • Passes through network of liver cells • Bile collected flows from the centre to periphery of liver

4. Liver cells • Majority of liver cells are hepatocytes • completes many of the functions of the liver • Bile exported from hepatocytes to bile canaliculito the bile duct of the portal triad • Sinosoidsare discontinuous capillaries • Deliver nutrients (of the GI tract) from portal vein to hepatocytes • Kupffer cells (derivative of macrophages) also found in capillaries

6. Physiology of the Liver • The liver is thought to participate in as many as 500 different functions, usually in association with other organs • Blood entering the liver brings nutrients and foreign substances from the GI tract, bilirubin from hemoglobin breakdown and metabolites from peripheral tissues • Functions can be summed up into six major categories: • Synthesis • Storage • Excretion • Filtration • Immune • Hemostasis

7. Carbohydrate Metabolism • The liver performs several key roles in carbohydrate metabolism: • Gluconeogenesis - the synthesis of glucose from pyruvate, lactate, citric acid cycle intermediates and most amino acids via the formation of oxaloacetate • Glycogenolysis - the breakdown of glycogen into glucose • Glycogenesis - the formation of glycogen from glucose glycogen(n residues) + Pi  glycogen(n-1 residues) + glucose-1-P

8. Amino Acid Synthesis • The set of biochemical processes that occur in the production of amino acids from other compounds • Ammonia is the source of nitrogen for all amino acids • Carbon backbones (-ketoacids) are obtained from the glycolytic pathway, pentose phosphate pathway or citric acid cycle

9. Protein Synthesis • Hepatocytes are responsible for synthesis of many proteins • Albumin – most abundant plasma protein is synthesized almost exclusively in the liver • Insulin-like growth factor 1 (IGF-1) – polypeptide protein hormone important in childhood growth • Thrombopoietin – glycoprotein hormone that regulates production of platelets • Angiotensinogen – hormone responsible for raising blood pressure • The liver synthesizes many of the clotting factors necessary for blood coagulation • Coagulation factors I (fibrinogen), II (prothrombin), V, VII, IX, X, XI, protein C, protein S and antithrombin • Hepatocytes are also responsible for the breakdown of insulin and many other hormones

10. Immunology • Lymphocyte population is enriched in natural killer cells and natural killer T cells • First line immune defense • Modulation of liver injury • Recruitment of circulating lymphocytes • Specialized macrophages called Kuppfer cells line the sinusoids • Important role in digesting invading bacteria, fungi, parasites, worn-out blood cells and cellular debris

11. Storage • The liver stores many nutrients, vitamins and minerals • Glucose is transported into liver cells where it is stored as glycogen • Rates at which glycogen is synthesized by glycogen synthase and degraded by glycogen phosphorylase are controlled by levels of their allosteric effectors (ATP, AMP, G6P and glucose) • Vitamins A, D, E, K and B12 • Copper • Iron, stored as ferritin or hemosiderin

12. Liver produces bile • Liver secretes 600 -1200 mL of bile daily. • Bile salts emulsify fats and fat soluble vitamins by creating micelles. • Bile serves as a vehicle for excretion of bilirubin, excess cholesterol and metabolic end products which cannot be excreted by urine.

13. Composition of bile Cholic Acid Bilirubinglucuronide

14. Enterohepatic Circulation *95% of the Bile acids get reabsorbed and cycle back to the liver

15. Bilirubin elimination Bilirubin is formed during the breakdown of senescent red blood cells. Insoluble bilirubin travels to the liver hepatocytes where it is glucoronidated and released into the intestine as a constituent of bile. In intestine, bilirubin is converted into a highly soluble substance called urobilinogen by intestinal flora – excreted via feces. Small proportion (~5%) gets reabsorbed and excreted via urine.

16. Lipid Metabolism Certain aspects of lipid metabolism occur mainly in the liver. These include: The oxidation of fatty acids to supply energy for other body functions; To derive energy from neutral fats (triglycerides), the fat must first be split into glycerol and fatty acids, and then the fatty acids split into acetyl-coenzyme A (acetyl-CoA). Acetyl-CoA can be used by the liver to produce adenosine triphosphate (ATP) or it can be converted to acetoacetic acid and released into the bloodstream and transported to other tissues, where it is used for energy. The synthesis of large quantities of cholesterol, phospholipids, and most lipoproteins; The formation of triglycerides from carbohydrates and proteins.

17. Drug Metabolism in the Liver • Perfused by the portal vein, first organ exposed to foreign substances • Houses a specific set of enzymes dedicated to modifying chemical entities (known as the first-pass effect) • Microsomal enzymes: biotransformation and conjugation • Non-microsomal enzymes: acetylation, methylation, GSH conjugation, hydrolysis, etc...

18. Phase I: The Cytochrome P450 Oxidases • Oxidation, reduction and hydrolysis • R-H R-OH • Heme-containing proteins found primarily in smooth ER of liver microsomebut also in SI/kidney • Many isozymes with different, but somewhat overlapping specificity • Phase I soluble (cytosolic) enzymes: alcohol/aldehydedehydrogenase, epoxidehydrolase, esterase, etc... • Flavin-containing mono-oxidases oxidizes heteroatoms (S and N) NADPH + H+ NADP + + H2O CYP3A4

19. Phase II: Conjugation Reactions • Only found in liver (smooth ER and cytosol) • Facilitate excretion of metabolites by the kidney

20. Summary • Liver made of repeating units of lobules which connect to vasculature via portal triad and central vein • Liver cells are called hepatocytes • The liver has up to 500 different functions which can be summed up into six major categories: synthesis, storage, excretion, filtration, immune and hemostasis • The liver plays a major role in carbohydrate metabolism and maintaining blood glucose levels through gluconeogenesis, glycogenolysis and glycogenesis • Liver produces bile to solubulize fats and excrete metabolites. • Liver is involved in breakdown and synthesis of lipids and other by-products • Liver is the primary site of drug metabolism in the body, first pass metabolism • Phase I cytochrome p450-mediated and phase II conjugation reactions promote excretion of metabolites

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