{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T08:51:20Z","timestamp":1790412680645,"version":"4.1.0"},"reference-count":14,"publisher":"S. Karger AG","issue":"1","license":[{"start":{"date-parts":[[2011,1,1]],"date-time":"2011-01-01T00:00:00Z","timestamp":1293840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"},{"start":{"date-parts":[[2011,1,1]],"date-time":"2011-01-01T00:00:00Z","timestamp":1293840000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Dig Dis"],"published-print":{"date-parts":[[2011]]},"abstract":"<i>Background:<\/i> Cholangiocytes expose a striking resistance against bile acids: while other cell types, such as hepatocytes, are susceptible to bile acid-induced toxicity and apoptosis already at micromolar concentrations, cholangiocytes are continuously exposed to millimolar concentrations as present in bile. We present a hypothesis suggesting that biliary secretion of HCO<sub>3<\/sub><sup>\u2013<\/sup> in man serves to protect cholangiocytes against bile acid-induced damage by fostering the deprotonation of apolar bile acids to more polar bile salts. Here, we tested if bile acid-induced toxicity is pH-dependent and if anion exchanger 2 (AE2) protects against bile acid-induced damage. <i>Methods:<\/i> A human cholangiocyte cell line was exposed to chenodeoxycholate (CDC), or its glycine conjugate, from 0.5 m<i>M<\/i> to 2.0 m<i>M<\/i> at pH 7.4, 7.1, 6.7 or 6.4, or after knockdown of AE2. Cell viability and apoptosis were determined by WST and caspase-3\/-7 assays, respectively. <i>Results:<\/i> Glycochenodeoxycholate (GCDC) uptake in cholangiocytes is pH-dependent. Furthermore, CDC and GCDC (pK<sub>a<\/sub> 4\u20135) induce cholangiocyte toxicity in a pH-dependent manner: 0.5 m<i>M<\/i> CDC and 1 m<i>M<\/i> GCDC at pH 7.4 had no effect on cell viability, but at pH 6.4 decreased viability by >80% and increased caspase activity almost 10- and 30-fold, respectively. Acidification alone had no effect. AE2 knockdown led to 3- and 2-fold enhanced apoptosis induced by 0.75 m<i>M<\/i> CDC or 2 m<i>M<\/i> GCDC at pH 7.4. <i>Discussion:<\/i> These data support our hypothesis of a biliary HCO<sub>3<\/sub><sup>\u2013<\/sup> umbrella serving to protect human cholangiocytes against bile acid-induced injury. AE2 is a key contributor to this protective mechanism. The development and progression of cholangiopathies, such as primary biliary cirrhosis, may be a consequence of genetic and acquired functional defects of genes involved in maintaining the biliary HCO<sub>3<\/sub><sup>\u2013<\/sup> umbrella.<\/jats:p>","DOI":"10.1159\/000324687","type":"journal-article","created":{"date-parts":[[2011,6,20]],"date-time":"2011-06-20T07:14:47Z","timestamp":1308554087000},"page":"62-65","source":"Crossref","is-referenced-by-count":26,"title":["Biliary Bicarbonate Secretion Constitutes a Protective Mechanism against Bile Acid- Induced Injury in Man"],"prefix":"10.1159","volume":"29","author":[{"given":"Simon","family":"Hohenester","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Maillette de Buy Wenniger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas M.","family":"Jefferson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald P.","family":"Oude Elferink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Beuers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"127","published-online":{"date-parts":[[2011,6,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.jhep.2008.07.027"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1002%2Fhep.510250104"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1016%2FS0016-5085%2899%2970564-0"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1053%2Fjhep.2002.33634"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.jhep.2008.09.010"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1002%2Fhep.23810"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1074%2Fjbc.M804585200"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.3748%2Fwjg.15.1677"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.1172%2FJCI116546"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.jhep.2010.05.015"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1002%2Fhep.22789"},{"key":"ref12","doi-asserted-by":"publisher","DOI":"10.1053%2Fgast.1996.v110.pm8612999"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1371%2Fjournal.pone.0012403"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1053%2Fj.gastro.2007.08.020"}],"container-title":["Digestive Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/324687","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/324687","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T19:33:57Z","timestamp":1745436837000},"score":1,"resource":{"primary":{"URL":"https:\/\/karger.com\/article\/doi\/10.1159\/000324687"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011]]},"references-count":14,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2011,6,1]]},"published-print":{"date-parts":[[2011,6,20]]}},"URL":"https:\/\/doi.org\/10.1159\/000324687","archive":["Portico"],"relation":{},"ISSN":["0257-2753","1421-9875"],"issn-type":[{"value":"0257-2753","type":"print"},{"value":"1421-9875","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011]]}}}