ENVR 430

Hepatic Physiology and Toxicology

Nov 15, 2006

Jane Ellen Simmons, 919-541-7829

Simmons.Jane@epa.gov

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