title: The biliary HCO(3)(-) umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies.
abstract: This review focuses on the hypothesis that biliary HCO(3)(-) secretion in humans serves to maintain an alkaline pH near the apical surface of hepatocytes and cholangiocytes to prevent the uncontrolled membrane permeation of protonated glycine-conjugated bile acids. Functional impairment of this biliary HCO(3)(-) umbrella or its regulation may lead to enhanced vulnerability of cholangiocytes and periportal hepatocytes toward the attack of apolar hydrophobic bile acids. An intact interplay of hepatocellular and cholangiocellular adenosine triphosphate (ATP) secretion, ATP/P2Y- and bile salt/TGR5-mediated Cl(-)/ HCO(3)(-) exchange and HCO(3)(-) secretion, and alkaline phosphatase-mediated ATP breakdown may guarantee a stable biliary HCO(3)(-) umbrella under physiological conditions. Genetic and acquired functional defects leading to destabilization of the biliary HCO(3)(-) umbrella may contribute to development and progression of various forms of fibrosing/sclerosing cholangitis.
authors: Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. u.h.beuers@amc.uva.nl
authors: Ulrich
authors: U
authors: Beuers
authors: Simon
authors: S
authors: Hohenester
authors: Lucas J Maillette
authors: LJ
authors: de Buy Wenniger
authors: Andreas E
authors: AE
authors: Kremer
authors: Peter L M
authors: PL
authors: Jansen
authors: Ronald P J Oude
authors: RP
authors: Elferink
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism / Q000633:toxicity; D001652:Bile Ducts / Q000378:metabolism*; D027963:Chloride-Bicarbonate Antiporters / Q000502:physiology*; D015209:Cholangitis, Sclerosing / Q000188:drug therapy* / Q000209:etiology* / Q000503:physiopathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008823:Micelles; D010743:Phospholipids / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000502:physiology*
chemical_list: D001639:Bicarbonates; D001647:Bile Acids and Salts; D027963:Chloride-Bicarbonate Antiporters; D008823:Micelles; D010743:Phospholipids; D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate