What are the major functions of the liver?
What are the main cell types of the liver?
hepatocytes (80%)- responsible for most of the metabolism, excretion, etc.
stellate- function unknown but they induce fibrosis in many liver
sinusoidal endothelial cells line the sinuosoids
70% of the blood supply to the liver comes from where?
The portal vein (and this can increase up to 90% after a meal)
There is a single central vein in each liver lobule which then drains to the hepatic vein, and
Describe the path of bile from hepatocytes into the duodenum
bile is produced by hepatocytes and secreted into canaliculi between hepatocytes which join together to form interlobular ducts which joint together to form the right and left hepatic ducts which then combine to form the common hepatic duct which joins with the cystic duct from the gallbladder and then the main pancreatic duct to drain into the duodenum at the spincter of oddi (that is normally closed but opens after meals)
T or F. Bile is continuously secreted by hepatocytes even between meals
T. Although in less amounts than following a meal
What is the composition of bile secreted from the hepatocytes initially?
Mainly bile acids (and cholesterol and phospholipids), and electrolytes such as Ca2+, K+, Cl-, and Na+ in similar concentrations to plasma along with water.
Note that once its secreted into the interlobular ducts, the epithelial cells of the ducts change the compositon
How do bile interlobular ducts change the composition of the initial bile? What stimulates it?
epithelial cells secrete HCO3-, Na+, and H2O in a process similar to that of pancreatic ductal cells (active transport with Cl-/HCO3- exchangers, etc.)
This process is stimulated by Secretin via increasing cAMP
Describe the flow of bile between meals
In between meals the spincter of Oddi is closed so very little bile enters the duodenum, so the vast majority backs up into the gallbladder (which can distend due to smooth muscle relaxation).
Also note that the gallbladder can concentration the bile by reuptake of electrolytes, water, etc.
What happens to the VAST majority of bile acids once they reach the ileum?
they are reabsorbed via enterohepatic recirculation into portal blood back to the liver via hepatocyte uptake
What are the main components of bile?
1. Bile acids (many kinds used for digestion/absorption of lipids and activation of enzymes for digestion)
2. Phospholipids (majorly lecithin to help solublize bile acids)
3. Cholesterol (only because it is excreted when storages increase)
4. Bile pigments (like bilirubin from heme breakdown for excretion- no other function- accumulation would be toxic)
5. Inorganic ions (like HCO3- via secretin stimulation, which acts to neutralize acid in the duodenum)
What are bile acids synthesized from?
cholesterol via 7a-hydroxylase (rate-limiting) to form the primary bile acids chenodeocycholic acid (2) and then cholic acid (4; most soluble due to 3 -OH groups) in the hepatocytes in the liver, and then to secondary bile acids deoxycholic acid (1) and lithocholic acid (trace; least soluble) in the small intestine via bacterial action
What main things determine the solubilty of bile acids?
1) No. of hydroxy groups (more= more soluble)
2) Ionization of carboxyl group (more ionized= more soluble)
What is the purpose of conjugating bile acids with glycine or taurine in the liver?
they increase the ionization of the carboxyl group and thus increase solubility
T or F. Bile acids are amphipathic
What happens to bile acids at high concentrations?
they can aggregate to form micelles due to their amipathic nature
NOTE: micelles form at the "critical micellar concentration"
Describe the phospholipids present in bile and their function
they are amphipathic (choline and phosphate are hydrophilic and fatty acids are hydrophobic)
insoluble in the absence of bile salts (but in the presence of bile salts can form soluble mixed micelles)
Describe the cholesterol in bile
very hydrophobic, weakly polar, and will not form micelles alone but can in the presence of phospholipids and bile acids to become soluble
This helps the complex to become soluble!
Heme results from breakdown of old RBCs. How is bilirubin formed from heme for excretion?
Heme oxygenase opens the structure and oxidizes it using NADPH to release CO and Fe2+ to form biliverdin, and then bilverdin reductase uses NADPH to form bilirubin
This occurs in the reticular endothelial cells!
What happens once bilirubin is formed in the reticular endothelial cells?
It is secreted into plasma where it is bound by ALBUMIN (b/c its insoluble) to travel to the liver where it taken up and conjugated to become more soluble (dont form micelles) for excretion
NOTE: When liver functioning is impaired, serum bilirubin increases leading to jaundice
The rate of bile secretion varies depending on the amount of ______ in the liver
bile acids re-entering the liver through enterohepatic recirculation
Note that although most bile acid in the liver recirulates, a small amount is lost in feces and thus 7a-hydroxylase constantly produces a low level of bile acids
Bile is stored in the ______ between meals
gallbladder. After a meal the gallbladder contracts and the Spincter of Oddi opens to release bile
What causes the gallbladder to contract and the spincter of Oddi to open during/after a meal?
acid entering the duodenum causes release of CCK which stimulates both
Notice how they peak at around 1 hr and last all 4 hrs AND enteroheaptic recirulation is IN TACT
E.H.C. is interrupted= hardly and bile acids
How are bile acids reabsorbed from the portal vein?
there are active transporters called NTCP (Sodium taurylated co-transporter) that co-transport Na and B.A. from the basolateral membrane and Na is recycled via a NaKATPase (or via non-specific OATPs!!) and then B.A. crosses the apical membrane via Bsep channels (note that B.A.s are always protein bound)
Notice the passive diffusion of the others
T or F. B.A. reabsorption in the liver is almost 100% efficient
T. It only requires one pass with the NTCP and OATPs
Some bile acids are reabsorbed passively in the ileum but the majority are reabsorbed actively via Na-coupled ASBT channel
What molecule provides negative feedback on CYP7A1 in the hepatocytes (7a-hydroxylase)?
When high levels of bile acids are reabsorbed into the ileal enterocytes, they can induce gene transcription of FGF19, which inhibits 7a-hydroxylase
Describe circulation of bilirubin
The reticulo-endothelial cells produce bilirubin from heme/old RBCs where it is released into plasma bound to albumin (not soluble alone) where it taken up by the liver via cMOAT transporters and conjugated with glucuronic acid to form bilirubin glucuronide and make them more soluble. This is then secreted into the intestine via MRP2 channels where it is deconjugated by bacteria, and then bilirubin is acted on by H2 to form urobiliogen which is mainly excreted in feces and some is recirculated via portal blood to the liver, where most of that re-enters the same cycle for fecal excretion and a small amount enters systemic blood to the kidneys where it is oxidized into urobilin in urine (turns it yellow)
Note that only the hepatocyte secretions of bile is bile-acid dependent, not the ductal contributions (which add more HCO3- and Na and H20) (aka bile acid independent secretions)
In the gallbladder bile is concentrated further!
What does the gallbladder do?
It undergoes smooth-muscle receptive distension of bile and concentrates it up to 20x in between meals
Note that all of the H+ and HCO3- exiting the gallbladder epithelium into the lumen are transformed into H2O and CO2 and then fully absorbed so that the gallbladder:
decreases Na, Cl, AND H2O
How does CCK stimulate gallbladder contraction?
Again, CCK is released when gastric content enters the duodenum and acts via:
1) Direct diffusion to the gallbladder to cause contraction
2) Vagal efferent stimlation of the dorsal vagal complex to promote Ach meidated contraction of the gallbladder and NO/VIP mediated relaxation of the spincter of Oddi
Composition changes the longest it sites in the gallbladder! Notice how concentrated B.A. and Na+ gets
Cholesterol is not very soluble, so if theres too much then phospholipids and bile acids cannot keep it soluble in the case of cholesterol stones. The result of low bile acids is worse digestion of lipids, AAs, etc. due to the too low pH of the duodenum leading to digestive enzymes not being activated (leading to steatorrhea or osmotic diarrhea)
Pigment stones- remember that bilirubin is not soluble unless conjugated to (glucuronide) but in pathology, deconjugation can occur via B-glucuronidase which is present normally in the gallbladder wall when bacteria/trauma damage the gallbladder wall and expose it to bilirubin (NOTE: E. coli also express B-glucuronidase)