Bile Formation

Bile formation is an osmotic secretory process that is driven by the active concentration of bile salts in the bile canaliculi. Bile acids are produced from cholesterol and prior to being excreted from hepatocytes are bound to specific amino acids allowing them to exist as bile salts. One side of the bile salt molecule is negatively charged (hydrophilic) whilst the other is hydrophobic allowing bile salts to form micelles once a certain bile salt concentration has been reached.

Various transport mechanisms in the basolateral (sinusoidal) and apical (canalicular) surfaces of the hepatocytes facilitate this active concentration. The rate limiting step in this process is via transport across the canalicular membrane side of the hepatocyte and specifically via ATP-dependent pumps (ATP-binding cassette family of membrane transporters).

Within the sinusoidal membrane, Na/K ATPase maintains a –35mV charge which drives several transport mechanisms. The Na/H+ pump drives protons out of the cell whilst HCO3- is exhanged for Na+ facilitating the entry of bicarbonate. Therefore active concentration of bile salts or acids is Na+ dependent and transport from the plasma into hepatocytes is mediated by the sodium taurocholate cotransporter. Other non-conjugated bile salt (cholate) and lipophilic albimin-bound compounds are transported from plasma into hepatocytes via a sodium-independent transporter.

A number of transporters have been identified as important in bile formation. The multidrug resistance-1 P-glycoprotein (MDR1) and MDR3 have liver specific functions allowing them to transport phosphatidylcholine from the inner to the outer leaflet of the canalicular membrane. The Canalicular multispecific organic-anion transporter is a canalicular form of the multidrug resistance-associated protein (MDP2) and mediates the transport of leukotriene C4, glutathione-S conjugates and glucuronides (bilirubin diglucuronide, estrodiol-17β- glucuronide) and is largely responsible for generation of bile flow independent of bile salts within the bile canaliculi. Canalicular bile salt transporters are thought to be members of the ATPase binding cassette family.

Bile flow is also affected by a number of other variables including the exocytosis of transcytotic and subcanalicular vesicles, activities of peptidases, nulceotidases, periodic contractions of bile canaliculi, bile ductules and hepatocyte ion channels. Chloride is excreted by the chloride/bicarbonate anion exchanger and the cystic fibrosis transmembrane regulator (CFTR) which is found on the luminal surface of the bile duct epithelial cells.

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