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ENVR 430
Hepatic Physiology and Toxicology
Nov 15, 2006
Jane Ellen Simmons, 919-541-7829
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.
B. Cell surfaces. Three cell surfaces, different composition/function
- intercellular surface (the least interesting from a tox viewpoint)
- sinusoidal surface. Has lots of microvilla - it is adapted for absorption and secretion
- canalicular surface - the plasma membrane of the hepatocyte forms the beginning of the biliary tree
C. Functions
1. Protein Synthesisa. 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 factorsFibrinogenProthrombin
c. Glucose Storage and Release
Glucose (G) can cross the cell membrane - simple concentration gradient diffusion
G-6- phosphate can’t cross the cell membrane
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
d. Bile formation
The liver produces ~500 ml (1/2 liter) of bile daily
Major components of bile:WaterBile salts - formed from cholesterolBile pigments - produced by hemoglobin breakdown Cholesterol
Minor components of bile:Fatty acidsNa+HCO3Cl-K+
Functions of bile salts- fat emulsification- fatty acid absorption- absorption of the fat soluble vitamins (A, D, E, K)
Enterohepatic Circulationbile salts, bile pigments, kepone, arsenic
VII. 2. Cells of the Sinusoid
A. Endothelial CellsB. Ito CellsC. Pit CellsD. Kupffer Cells
(Not listed in order of importance/abundance!)
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.
B. Ito Cells
Are rare cell typesAre also known as fat-storing cells or stellate cells. Ito cells synthesize collagen (so have an important role in the development of cirrhosis.Ito cells are the major site for vitamin A storage in the body
C. Pit Cells
Pit cells are even more rare than Ito cells. Pit cells are 'a lymphocyte-type cell with anti-tumor activity'.
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).
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
What do Kupffer cells phagocytize:
* bacteria and other micro-organismsnormal GI tract microfloraexogenous (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 bloodRed Blood Cells – including hemoglobin
degradation
Kuppfer 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
AST = aspartate aminotransferase (a serum marker of hepatocyte damage)
GdCl3 = gadolinium chloride, an inhibitor of Kupffer cell function
From Edwards et al., Toxicology and Applied Pharmacology, 119:275-279, 1993.
Nitrocatechol formation is a sensitive marker for CYP2E1 activity; CYP2E1 is 450 isoform that converts CCl4 (nontoxic) to the CCl● (trichloromethyl radical, toxic).(from Edwards et al., TAP, 1993)
ALT = alanine aminotransferase, a serum marker of hepatocyte damageMP = methylpalmitate, an inhibitor of Kupffer cell function
From ElSisi et al., TAP, 1993a and ElSisi et al., TAP, 1993b)
From ElSisi et al. TAP, 1993
VII. 3 Bile Duct CellsPrincipal function is modification of bile compositionReabsorption of Na+, K+, Cl-, H20Secretion of Na+, K+, Cl-, H20, HCO3-
Bile duct cells first appear in the terminal bile ductules