title: The Emerging Role of Soluble Adenylyl Cyclase in Primary Biliary Cholangitis.
abstract: BACKGROUND
  Primary biliary cholangitis (PBC; previously referred to as primary biliary cirrhosis) is a chronic fibrosing cholangiopathy with the signature of an autoimmune disease and features of intrahepatic cholestasis. Immunosuppressing treatments are largely unsuccessful. Responsiveness to ursodeoxycholic acid and reduced expression of anion exchanger 2 (AE2) on canalicular membranes and small bile ducts underline the importance of bicarbonate transportation in its disease mechanism. Soluble adenylyl cyclase (sAC; ADCY10) is an evolutionarily conserved bicarbonate sensor that regulates apoptosis, barrier function and TNF signaling. Key Messages: The biliary epithelium defends against the toxic bile by bicarbonate secretion and by maintaining a tight barrier. Passive diffusion of weak acid conjugates (e.g. bile salts and other toxins) across plasma membrane is pH-dependent. Reduced AE2 expression results in both reduced bicarbonate secretion and accumulation of bicarbonate in the cells. Increased intracellular bicarbonate leads to increased sAC activity, which regulates bile salt-induced apoptosis. Reduced bicarbonate secretion causes more bile salts to enter cells, which further increase sAC activity by releasing intracellular Ca2+ store. In vitro studies demonstrate that inhibition of sAC not only corrects sensitization to bile salt-induced apoptosis as a result of AE2 down-regulation but also prevents bile salt-induced apoptosis altogether. Targeting sAC is also likely to slow down disease progression by strengthening the barrier function of biliary epithelia and by reducing oxidative stress as a result of chronic inflammation.
  
  
  CONCLUSIONS
  sAC is a potential therapeutic target for PBC. More in vitro and in vivo studies are needed to understand how sAC regulates bile salt-induced apoptosis and to establish its therapeutic value in PBC and other cholestatic cholangiopathies.
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jung-Chin
authors.initials: JC
authors.lastname: Chang
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.forename: Ronald P J
authors.initials: RP
authors.lastname: Oude Elferink
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001639:Bicarbonates / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D002761:Cholangitis / Q000201:enzymology*; D006801:Humans; D008954:Models, Biological; D018384:Oxidative Stress
chemical_list: D001639:Bicarbonates; D001647:Bile Acids and Salts; D000262:Adenylyl Cyclases