Lecture 14 Flashcards
What are the properties of the liver?
Large tissue that is central to nutrient assimilation
Serves as a chemical factory
It is a excretory system and exocrine gland
It also has an endocrine gland
Also serves as a storage depot
What are the functions of the liver?
Working with the gallbladder, it enchances lipid absorption in the GI tract
Detoxifies endogenous & exogenous reactive compounds
Produces substances essential for circulatory function, including albumin, coagulation factors and lipoproteins
Stores, metabolizes, distributes nutrients, minerals, and vitamins
Converts T4 to T3 and initiated vitamin D hydroxylation
Produces and excretes bile to eliminate waste product
Slide 4
What is the liver structure?
Lobules of hepatocytes form a micro organ separating bile canaciculi from fenestrated endothelium (sinusoids)
Portal triad= hepatic artery, portal vein, and bile duct
Apical membrane faces canalicular lumen
Basolateral membrane faces the pericellular space between hepatocytes and sinusoids
Bile canaliculi are formed by the apical membranes of adjacent hepatocytes to form a chicken wire like structure that allows bile containing fluid movement
Slide 5
What is the blood flow through the liver?
75% of blood flow comes from the portal vein, 25% comes from the hepatic artery
Venues and arterioles form a sinusoidal network that drains into hepatic venules or central veins
Lymphatics and nerves run alongside the portal vein
Arterioles from hepatic artery feed bile ducts and rich capillary network
Slide 6
What are the 3 zones of the liver?
Zone I- closest to oxygen & solute rich blood
Zone II & III- receives lower oxygen and solutes
Zones are specified for different functions
Slide 7
How do hepatocytes synthesize bile acids?
Substrate is cholesterol, when endogenous levels of cholesterol are too high, this is the predominant mechanism by which to eliminate excess cholesterol
Main primary bile acids in humans are cholic acid and chenodeoxycholic
In GI tract, this will be converted into secondary bile acids, which are absorbed in the distal region of the small intestine or in the proximal colon
Slide 9
How is bile drained?
Human liver has >2km of ductules & ducts, forming a network between hepatocytes
Starting from the canaliculi, bile enters terminal ductules, then perilobular ducts and then interlobular, then hepatic duct
Hepatic duct merges with the cystic duct to form the bile duct
Bile duct merges with pancreatic duct
Slide 10
What are the 4 steps of excreting compounds into the bile tract?
- Import from blood
- Cellular transport
- Chemically modify or degrade
- Excrete into the bile tract
Slide 12
What are the mechanisms of bile salt and anion uptake into hepatocytes?
The sodium/taurocholate cotransporting polypeptide (NTCP) is predominant in the uptake of bile salts, as well as in the uptake of steroids
Sodium potassium pump provides driving force to transport compound
Organic anion transporting polypeptide (OATPs) mediated sodium independent uptake of amphipathic compounds such as steroids, bile acids, and drugs
Uncharged bile can enter hepatocytes through passive diffusion
Slide 12-13
What are the mechanisms of bilirubin uptake & excretion?
Hepatobiliary system is essential for excretion of degraded hemoglobin
If this doesn’t operate properly the person will develop jaundice, sign of liver dysfunction
Mechanism of unconjugated bilirubin uptake by heaptocytes is unknown but conjugated bilirubin uptake is mediated by OATP1B1 & OATP1B3
Slide 14
What is the mechanism of uptake and excretion for organic cations?
40% drugs are organic cations
Members of the organic cation transport (OCT) family mediate the uptake of diverse lipophilic organic cations
OCT1 and OCT3 perform this function in human hepatocytes
Excretion into the bile tract is performed by MDR1
Slide 15
What is the mechanism of excretion of biliary lipids and cholesterol?
Phosphatidylcholine is a major component of bile. Key role in micelle formation
MDR3 mediated the excretion of this lipid
Bile is also the main pathway for the elimination of excess cholesterol
Heterodimer of ABCG5 & ABCG8 are able to efflux cholesterol into bile
Slide 15
What are the 3 phases in which hepatocytes metabolize and detoxify compounds?
Phase 1- oxidation reduction reactions performed by cytochrome p450 enzymes make the compound more polar, generally through hydroxylation
Phase 2- further modification is performed via conjugation with agents such as sulfate, glucuronate, or glutathione to make the compounds more water soluble
Phase 3- modified compound can now be recognized and delivered to transporters for excretion. Can be to bile tract or back into the sinusoidal blood for excretion in the urine
Slide 16
What are the major components of bile flow?
Canalicular bile flow is the sum of a constant, bile acid independent flow and a flow that is dependant on the amount of bile being excreted
Total bile flow is the sum of canalicular bile flow and ductular secretions from cholangiocytes
The secretion of organic compounds drives bile acid independent flow
Bile salts are in micelles and form large polyanions which interact with soluble positively charged ions that establish the osmotic force for water movement
Slide 17
What is the regulation of ductular secretion cholangiocytes?
Cholangiocytes are the second major source of fluid in bile
Mechanism similar to pancreatic duct cells, they secrete a watery & bicarbonate rich fluid
Stimulated by secretion and other hormones in a cAMP dependant manner
Somatostatin lowers cAMP levels to inhibit secretions from cholangiocytes
Slide 18
