Bile acid interactions with cholangiocytes.
Cholangiocytes are exposed to high concentrations of bile acids at their apical membrane. A selective transporter for bile acids, the Apical Sodium Bile Acid Cotransporter (ASBT) (also referred to as Ibat; gene name Slc10a2) is localized on the cholangiocyte apical membrane. On the basolateral membrane, four transport systems have been identified (t-ASBT, multidrug resistance (MDR)3, an unidentified anion exchanger system and organic solute transporter (Ost) heteromeric transporter, Ostalpha-Ostbeta. Together, these transporters unidirectionally move bile acids from ductal bile to the circulation. Bile acids absorbed by cholangiocytes recycle via the peribiliary plexus back to hepatocytes for re-secretion into bile. This recycling of bile acids between hepatocytes and cholangiocytes is referred to as the cholehepatic shunt pathway. Recent studies suggest that the cholehepatic shunt pathway may contribute in overall hepatobiliary transport of bile acids and to the adaptation to chronic cholestasis due to extrahepatic obstruction. ASBT is acutely regulated by an adenosine 3', 5'-monophosphate (cAMP)-dependent translocation to the apical membrane and by phosphorylation-dependent ubiquitination and proteasome degradation. ASBT is chronically regulated by changes in gene expression in response to biliary bile acid concentration and inflammatory cytokines. Another potential function of cholangiocyte ASBT is to allow cholangiocytes to sample biliary bile acids in order to activate intracellular signaling pathways. Bile acids trigger changes in intracellular calcium, protein kinase C (PKC), phosphoinositide 3-kinase (PI3K), mitogen-activated protein (MAP) kinase and extracellular signal-regulated protein kinase (ERK) intracellular signals. Bile acids significantly alter cholangiocyte secretion, proliferation and survival. Different bile acids have differential effects on cholangiocyte intracellular signals, and in some instances trigger opposing effects on cholangiocyte secretion, proliferation and survival. Based upon these concepts and observations, the cholangiocyte has been proposed to be the principle target cell for bile acids in the liver.
Xia
Xuefeng
X
University of Texas at Houston Medical School, 6431 Fannin Street, MSB 4.234, Houston TX 77030, USA.
Francis
Heather
H
Glaser
Shannon
S
Alpini
Gianfranco
G
LeSage
Gene
G
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D017920:Antiporters / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism / Q000502:physiology*; D001652:Bile Ducts / Q000166:cytology* / Q000503:physiopathology; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D002779:Cholestasis / Q000473:pathology / Q000503:physiopathology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005704:Gallbladder / Q000166:cytology / Q000502:physiology; D022781:Hepatocytes / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D027981:Symporters / Q000378:metabolism
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D017920:Antiporters; D001647:Bile Acids and Salts; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter; C095122:multidrug resistance protein 3