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ENVR 430 Hepatic Physiology and Toxicology Fall, 2008 Jane Ellen Simmons, 919-541-7829 Simmons.Jane@epa.gov

ENVR 430 Hepatic Physiology and Toxicology Fall, 2008 Jane Ellen Simmons, 919-541-7829 Simmons.Jane@epa.gov. General Information A. Size and Location The liver is the largest internal organ, in both animals and humans. In humans, the liver is: ~2.5 % of body weight in adults

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ENVR 430 Hepatic Physiology and Toxicology Fall, 2008 Jane Ellen Simmons, 919-541-7829 Simmons.Jane@epa.gov

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  1. ENVR 430 Hepatic Physiology and Toxicology Fall, 2008 Jane Ellen Simmons, 919-541-7829 Simmons.Jane@epa.gov

  2. General Information • A. Size and Location • The liver is the largest internal organ, in both animals and humans. • In humans, the liver is: • ~2.5 % of body weight in adults • ~ 5% of body weight at birth • The adult human liver weighs • 1,500 gm ± 100 gm, males • 1,300 gm ± 100 gm, females

  3. In humans, the liver is a single organ divided into four distinct lobes: right lobe left lobe quadrate lobe caudate lobe Location: upper part of the abdomen. Upper margin at the level of the 5th rib; lower margin lies slightly below the rib cage on the right side of the body. The ribs provide mechanical protection of the liver from physical damage.

  4. II. Hepatic Regeneration The liver has a remarkably high capacity for regeneration. After hepatectomy (excision or removal of part of the liver), the human liver rebuilds itself at a rate of up to 100 gm/day. Up to 80% of the liver can be removed with no permanent impairment of liver function How does the liver regenerate? Two adaptive responses are used: a) hypertrophy - increase in cell size b) hyperplasia - cellular proliferation (increase in cell number)

  5. Hypertrophy - increase in cell size • results in increased organ size • no new cells, just larger cells • increased cell size: not due to cell swelling is due to increased structural components • two types physiologic pathologic • typical causes • increased functional demand • hormonal stimulation

  6. Hyperplasia • increased organ size due to new cells • two types hormonal hyperplasia compensatory hyperplasia • Mechanism a. increased local production of growth factors increased # of growth factor receptors activation of intracellular signaling pathways b. production of transcription factors genes turned on (cell cycle regulators) c. net result is cell proliferation • Regulated by nutrients, environmental cues • Characterized by mitoses, temporary structural disorganization

  7. II. The Liver as a Target Organ Factors that make the liver a common target for environmental chemicals and pharmaceutical agents. a) High metabolic capacity. The liver has a high concentration, relative to other organs, of xenobiotic-metabolizing enzymes, for example, the cytochrome P-450 monooxygenase system. b) Uptake and Concentration. The liver tends to concentrate compounds because: 1) Diffusion into hepatocyte enabled. The 'design' of the sinusoidal lining cells (thin, fenestrated epithelium) provides close contact between the chemicals carried in the blood and the hepatocytes. 2) Hepatocytes have a high concentration of membranes, increasing the ability to concentrate lipophilic compounds.

  8. 3) Chemicals may be concentrated in the liver due to the presence (concentration) of sinusoidal transporters that increase the hepatic extraction of the compounds carried by these transporters. c) Biliary secretion. a) Compounds eliminated by bile secretion can reach high concentrations in the liver. Examples include such metals as arsenic, copper, manganese, cadmium, selenium, gold and silver. b) Enterohepatic circulation can lead to high hepatic concentrations of chemicals Examples of compounds that undergo enterhepatic circulation: bile salts, bile pigments, cholesterol, kepone and arsenic

  9. d)Location of the liver and its Blood Supply Oral Route of Exposure. For those chemicals with an oral route of exposure, the hepatic blood supply leads to high exposure. Absorption from the GI tract into blood that flows into the portal vein, which perfuses the liver, leads to the liver being the first organ perfused by chemicals absorbed from the gut. Inhalation Exposure. The liver is highly perfused, receiving 20-25% percent of total cardiac output. Although much of this (~80%) is from portal perfusion (blood that goes to the liver from the heart via passage first through other GI tract organs), the remaining 20% is from 'direct' cardiac perfusion.

  10. IV. Portal Blood System The hepatic blood supply makes the liver particularly susceptible to toxic chemicals, because of a) its high rate of perfusion and b) the 'pass-through' the liver of the venous blood draining other GI tract organs. The liver receives between 1/4 and 1/5 of total cardiac output; this equal about 1500 ml/min in a 70 kg human. The liver receives both arterial and venous blood. The arterial blood enters the liver via the hepatic artery while the venous blood enters the liver via the portal vein. The hepatic artery is a branch of the celiac trunk which branches off from the aorta.

  11. The portal vein is the venous drainage of a number of different gastrointestinal structures, including: esophagus stomach spleen pancreas small intestine colon Pressure Blood Flow Oxygen Hepatic artery 120 mmHg 300 ml/min 20 ml/min Portal Vein 8-10 mmHg 1200 ml/min 40 ml/min

  12. Advantages (and Disadvantages) of a portal system of blood delivery to the liver A. Cleaning of the blood. The gut wall is leaky and micro-organisms (both endogenous and exogenous) pass fairly freely into the portal blood stream. These micro-organisms are removed from the blood, before they reach the systemic circulation, by passage through the liver. Nutrient buffering. Approximately 2/3 of the total glucose entering the liver via the portal vein is extracted by the liver, then stored, and released to the systemic circulation as needed.

  13. Xenobiotic metabolism: A double-edged sword. When the parent compound is the toxic moiety, metabolism often leads to a decrease in the toxic potency.

  14. When a metabolite is the toxic moiety, metabolism often leads to an increase in toxic potency. inactive parent compound  toxic metabolite

  15. V. Cell Types Hepatocytes Bile Duct Cells Endothelial Cells Kupffer Cells Ito Cells Pit Cells

  16. VI. Organizational/Functional Units of the Liver The relationship of hepatic cells, blood supply, blood flow, biliary system flow. A. Hepatic Lobule (Classical Structure) Three Areas of the Lobule 1. centrilobular / centrizonal / central 2. midzonal 3. periportal / peripheral Location and/or direction of: cells (hepatocyte, bile duct cell, endothelial cell [aka sinusoidal lining cell], Kupffer cell, Ito cell, Pit cell), central vein (terminal hepatic venule), portal triad (terminal hepatic artery, terminal hepatic vein, bile duct), sinusoid, blood flow, bile flow

  17. Liver Lobule

  18. B. Liver Acinus Three Areas of the Acinus Zone 1 (rough match with periportal area of the lobule) Zone 2 (rough match with midzonal area of lobule) Zone 3 (rough match with centrilobular area of lobule) Location and/or direction of: cells (hepatocyte, bile duct cell, endothelial cell [aka sinusoidal lining cell], Kupffer cell, Ito cell, Pit cell), central vein (terminal hepatic venule), portal triad (terminal hepatic artery, terminal hepatic vein, bile duct), sinusoid, blood flow, bile flow

  19. VI. C. Comparison of the Centrilobular and Periportal Areas Centrilobular (Zone 3)Periportal (Zone 1) (Relative to Periportal) (Relative to Centrilobular) dec. O2 (30-40 mm Hg, 4-5% O2) incr. O2 (~65 mm Hg, 9-13% O2) dec. nutrients incr. nutrients dec. xenobiotic conc incr. xenobiotic conc incr. P450 dec. P450 incr. P450IIE1 (cyp 2E1) dec. P450IIE1 (cyp 2E1) dec. ALT incr. ALT dec. alcohol dehydrogenase incr. alcohol dehydrogenase dec. bile salts incr. bile salts dec. mitochondria incr. Mitochondria (fatty acid oxidation, (fatty acid oxidation, gluconeogenesis gluconeogenesis ammonia detox) ammonia detox) dec. glutathione incr. glutathione dec. Kupffer cells # incr. Kupffer cells #

  20. VII. Cell Types/Functions. • VII.1. Hepatocytes • A. The predominant cell type of the liver. Hepatocytes comprise ~80% of the volume of the liver and represent ~60% of the total number of cells in the liver. There are ~250 billion hepatocytes in the adult liver. • Hepatoctye plasma membrane- three types of functions a. Barrier functions b. Transport functions c. Integrative functions

  21. C. Hepatocyte Plasma Membrane surfaces. • Three distinct surfaces, different composition/function • Sinusoidal surface • ~35 - 70% of the total hepatoctye plasma membrane surface area • Has lots of microvilli - adapted for function of absorption and secretion • Specialized function of hormone binding • Intercellular (contiguous) surface • ~ 15% - 50% of the total hepatoctye plasma membrane surface area • Responsible for intercellular communication • Gap junctions facilitate cell-to-cell movement of molecules without dilution by extracellular fluid

  22. C. Hepatocyte Plasma Membrane surfaces cont’d. C. Canalicular surface • ~ 13 - 15% of the total hepatoctye plasma membrane surface area • canalicular surface - the plasma membrane of the hepatocyte forms the beginning of the biliary tree • c. tight junctions surround the bile canaliculus • d. lipid fluidity of the canalicular surface is lower than the the sinusoidal surface

  23. C. Functions 1. Protein Synthesis a. Hepatocyte has the 'fingerprint' of a highly synthetic cell - Large Nucleus - Large Concentration of Endoplasmic reticulum - Large Concentration of Golgi complexes b. Synthesis of - Plasma proteins Albumin (120 - 200 mg/kg/day) Very low density lipoproteins - Blood coagulation factors Fibrinogen Prothrombin

  24. c. Glucose Storage and Release

  25. Glucose (G) can cross the cell membrane - simple concentration gradient diffusion G-6- phosphate can’t cross the cell membrane

  26. Enzymes Involved: Conversion of G to G-6-P - hexokinase - ‘common’ to all cells - glucokinase - ‘unique’ to the liver Both catalyze ONLY the forward reaction Conversion of G-6-P to G G-6-phosphatase Found in liver, kidney, brain Absent or only in low concentrations in brain and muscle

  27. d. Bile formation The liver produces ~500 ml (1/2 liter) of bile daily Major components of bile: Water Bile salts - formed from cholesterol Bile pigments - produced by hemoglobin breakdown Cholesterol Minor components of bile: Fatty acids Na+ HCO3 Cl- K+

  28. Functions of bile salts - fat emulsification - fatty acid absorption - absorption of the fat soluble vitamins (A, D, E, K) Enterohepatic Circulation bile salts, bile pigments, kepone, arsenic

  29. VII. 2. Cells of the Sinusoid A. Endothelial Cells B. Stellate Cells C. Pit Cells D. Kupffer Cells (Not listed in order of importance/abundance!)

  30. A. Endothelial Cells (Sinusoidal Lining Cells) They are designed to provide little hindrance to to movement of molecules from the sinusoid to the hepatocyte. The lack a basement membrane, they have numerous fenestrae. Sinusoidal lining cells are narrow and thin relative to the endothelial cells that line other capillary beds, while the sinusoids themselves are larger than in most other capillary beds.

  31. Endothelial Cells (Sinusoidal Lining Cells) cont’d. • Fenestrae (FN) occupy 6-8% of the endothelial cell surface • Periportal (PP) and centrilobular (CL) differences CL slight decrease in FN diameter CL increase in FN number Net result is increase in porosity as move from PP to CL region • High endocytotic capacity Numerous endocytotic vesicles present Uptake by receptor-mediated endocytosis

  32. Stellate Cells • Previously called Ito cells, fat-storing cells, lipocytes, perisinusoidal cells • Not easily viewed on routine H&E staining • ~15% of total liver cell population • Major site of Vitamin A storage in the body • Heterogeneity along the sinusoid (periportal to centrilobular) • Become activated in liver injury a. initiation b. perpetuation Change from a quiescent cell to a proliferative, fibrogenic, contractile cell Vitamin A lost from activated Stellate cells

  33. Stellate Cells cont’d 7. Fibrosis results - deposition of scar matrix, loss of fenestrae from sinusoidal lining cells and loss of microvilli from sinusoidal surface of the hepatocyte. 8. What happens to activated stellate cells when liver injury resolves? revert back to ‘unactivated’ stellate cells? removed by apoptosis?

  34. Pit Cells • Pit cells are 'a lymphocyte-type cell with anti-tumor activity'. • Are natural killer cells – i.e. don’t require sensitization or activation • Originate from blood natural killer cells • ‘settle’ into hepatic sinusoid • First become high density Pit cells • High density Pit cells become Low density Pit cells • Low density Pit cells are more cytotoxic than High Density Pit cells which are more cytotoxic than natural killer cells against tumor cells.

  35. D. Kupffer cells. Kupffer cells are about 10% of the total cell population of the liver. There is a concentration gradient of Kupffer cells along the sinusoid, with higher numbers located in the periportal area. Kupffer cells belong to the monnuclear-phagocytic system (also known as the reticulo-endothelial system).

  36. Kupffer cells are: - sessile macrophages - are a source of cytokines - can act as antigen-presenting cells - are intensely phagocytic. Phagocytosis is a major function. Phagocytosis - recognition of foreign object - induction of phagocytosis - engulfment and formation of phagosome - fusion of phagosome with the lysosome - digestion

  37. What do Kupffer cells phagocytize: * bacteria and other micro-organisms normal GI tract microflora exogenous (i.e. environmental) bacteria and microorganisms * fibrin and its degradation products consequence of failure to remove fibrin consequence of too rapid removal of fibrin (??) * antigens and antibody complexes * dead or dying cells that circulate in the blood Red Blood Cells – including hemoglobin degradation

  38. Kupffer cells also function to modulate hepatocyte toxicity. They are intimately involved in carbon tetrachloride toxicity The play a vital role in the mechanism of vitamin A potentiation of carbon tetrachloride toxicity

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