1. CELLULAR ARCHITECTURE AND PHYSIOLOGY OF THE LIVER PHM 142 November 10, 2015 Ivan Nayve, (Calvin) Ho Lau, Adrienne Pham, Mathew Luen PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. OUTLINE Anatomy and Histology Hepatic Vascular System Liver Physiology Carbohydrate Metabolism Alcohol Detoxification 2

3. THE LIVER Heaviest gland in the body (~3lb) Performs over 500 metabolic functions Located inferior to the diaphragm in the upper right region of the abdomen 3

4. ANATOMY OF THE LIVER Vanputte et al. (2011) Seeley’s Anatomy and Physiology, 9 th edition. McGraw Hill, New York. 4

5. CELL TYPES 80% hepatocytes Major functional cell of the liver Specialized epithelial cells with a wide range of functions Single cell layer form hepatic laminae Ballet F. (1990) Hepatic circulation: potential for therapeutic intervention. Pharmac Ther 47: 281-328. 5

6. CELL TYPES 20% nonparenchymal cells Sinusoidal endothelial cells Small fenestrations for diffusion Endocytosis and secretion Kupffer cells Macrophages with endocytotic function Immune defense Pit cells Large granular lymphocytes Antiviral liver defense Stellate (Ito) cells Main source of ECM components Vitamin A storage 6 Bouwens et al. (1992) Liver cell heterogeneity: functions of non-parenchymal cells. Enzyme. 46: 155-168.

7. THE HEPATIC PORTAL CIRCULATION Directs blood from small intestine, stomach, pancreas and spleen to the liver Ballet F. (1990) Hepatic circulation: potential for therapeutic intervention. Pharmac Ther 47: 281-328. Vanputte et al. (2011) Seeley’s Anatomy and Physiology, 9 th edition. McGraw Hill, New York. 7 75% of blood entering liver is nutrient rich venous blood

8. THE HEPATIC PORTAL CIRCULATION 25% of blood enters liver as oxygenated arterial blood Ballet F. (1990) Hepatic circulation: potential for therapeutic intervention. Pharmac Ther 47: 281-328. Tortora et al. (2009) Principles of anatomy and physiology, 12 th edition. John Wiley & Sons Inc., New Jersey. 8

9. FUNCTIONS 1.Bile production – ↑ pH, emulsify fat 2.Storage – carbohydrates, vitamins, fat, copper, iron 3.Carbohydrate Metabolism 4.Detoxification – ammonia, alcohol 5.Phagocytosis – Kuppfer cells – worn out RBC’s, bacteria 6.Synthesis of proteins (albumin, fibrinogen, lipoproteins) 7.Metabolism of drugs (first-pass effect) 8.Activation of Vitamin D 9.Embryonic haematopoiesis 10.Excretion of bilirubin Vanputte et al. Seeley’s Anatomy and Physiology, 9 th edition. McGraw Hill, New York, 2011. 9

10. CARBOHYDRATE METABOLISM Glycogen Synthesis Blood glucose taken up by hepatocytes and converted to glycogen for storage Liver expresses Glycogen Synthase, an enzyme required for glycogen synthesis 10

11. GLYCOGENOLYSIS AND GLUCONEOGENESIS Glycogenolysis Glycogen is broken down to form glucose which can be released into the blood Gluconeogensis De novo synthesis of glucose from non-carbohydrate sources such as amino acids, lactate, and glycerol 11 GLYCOGEN AMINO ACIDS, LACTATE, GLYCEROL GLUCOSE

12. GLYCOGENOLYSIS AND GLUCONEOGENESIS 12

13. 13 ALCOHOL METABOLISM IN HEPATOCYTE Hepatocyte is the major site of alcohol metabolism 1. Ethanol is oxidized to acetaldehyde by alcohol dehydrogenase (ADH) This reaction is catalyzed by NAD + /NADH 90% of alcohol present in the liver is oxidized through this reaction Modified from: Bullock, C. (1990), The biochemistry of alcohol metabolism — A brief review. Biochemical Education, 18: 62–66.

14. 14 The same conversion can also be performed by the Microsomal Ethanol-Oxidizing System (MEOS) – this accounts for the remaining 10% It involves cytochrome P450 oxidase enzymes – in particular the CYP2E1 enzyme Ethanol is oxidized to acetaldehyde while O 2 is reduced to form H 2 O and NADPH is used as a hydrogen donor, forming NADP + This reaction requires hydrolysis of ATP

15. 2. Acetaldehyde is oxidized to acetate by aldehyde dehydrogenase (ALDH) This reaction is catalyzed by NAD + /NADH (NAD + acts as a cofactor) This occurs in the mitochondria and the resulting acetate is released into the bloodstream to be further oxidized into CO 2 and water in the peripheral tissues 15

16. 16 SUMMARY Liver composed of 80% hepatocytes (main functional unit) 20% are non-parenchymal cells: Blood delivery to the liver is through the portal vein (nutrient-rich) and the hepatic artery (oxygen-rich) and mixes in the liver sinusoids Carbohydrate metabolism in the liver includes glycogen synthesis, glycogenolysis and gluconeogenesis Ethanol is first oxidized to acetaldehyde by alcohol dehydrogenase. Acetaldehyde is further oxidized into acetate by aldehyde dehydrogenase. Acetate will enter the bloodstream and be oxidized and removed in the form of H 2 O and CO 2. Cell TypeFunction Sinusoidal Endothelial cellsEndocytosis and secretions Kupffer cellsPhagocytosis Pit cellsAntiviral defense Ito cellsVitamin A storage

17. REFERENCES Ballet F. (1990) Hepatic circulation: potential for therapeutic intervention. Pharmac Ther 47: 281-328. Bouwens et al. (1992) Liver cell heterogeneity: functions of non-parenchymal cells. Enzyme. 46: 155-168. Bullock, C. (1990) The biochemistry of alcohol metabolism — A brief review. Biochemical Education, 18: 62–66. Postic et al. (2004) Role of the liver in the control of carbohydrate and lipid homeostasis. Tortora et al. (2009) Principles of anatomy and physiology, 12 th edition. John Wiley & Sons Inc., New Jersey. Vanputte et al. (2011) Seeley’s Anatomy and Physiology, 9 th edition. McGraw Hill, New York. 17