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The aim of this study is to determine the physiological relevance of Car14 for biliary fluid and acid\/base output, as well as its role in the maintenance of hepatocellular and cholangiocyte integrity. The common bile duct of anesthetized <jats:italic>car14<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and <jats:italic>car14<\/jats:italic><jats:sup>+<jats:italic>\/<\/jats:italic>+<\/jats:sup> mice was cannulated and hepatic HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> output was measured by microtitration and bile flow gravimetrically before and during stimulation with intravenously applied tauroursodeoxycholic acid (TUDCA). Morphological alterations and hepatic damage were assessed histologically and immunohistochemically in liver tissue from 3- to 52-week-old <jats:italic>car14<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and <jats:italic>car14<\/jats:italic><jats:sup>+<jats:italic>\/<\/jats:italic>+<\/jats:sup> mice, and gene and\/or protein expression was measured for pro-inflammatory cytokines, fibrosis, and cholangiocyte markers. Biliary basal and more so TUDCA-stimulated HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> output were significantly reduced in <jats:italic>car14<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice of all age groups, whereas bile flow and hepatic and ductular morphology were normal at young age. <jats:italic>Car14<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice developed fibrotic and proliferative changes in the small bile ducts at advanced age, which was accompanied by a reduction in bile flow, and an upregulation of hepatic cytokeratin 19 mRNA and protein expression. Membrane-bound Car14 is essential for biliary HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> output, and its loss results in gradual development of small bile duct disease and hepatic fibrosis. Bile flow is not compromised in young adulthood, suggesting that Car14-deficient mice may be a model to study the protective role of biliary canalicular HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> against luminal noxi to the cholangiocyte.<\/jats:p>","DOI":"10.1007\/s00424-021-02659-3","type":"journal-article","created":{"date-parts":[[2022,2,4]],"date-time":"2022-02-04T13:03:01Z","timestamp":1643979781000},"page":"529-539","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Loss of luminal carbonic anhydrase XIV results in decreased biliary bicarbonate output, liver fibrosis, and cholangiocyte proliferation in mice"],"prefix":"10.1007","volume":"474","author":[{"given":"Zhenzhen","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajie","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Archana","family":"Kini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitte","family":"Riederer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorothee","family":"R\u00f6mermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerolf","family":"Gros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Seidler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,2,4]]},"reference":[{"key":"2659_CR1","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1002\/bip.22456","volume":"101","author":"V Alterio","year":"2014","unstructured":"Alterio V, Pan P, Parkkila S, Buonanno M, Supuran CT, Monti SM, De Simone G (2014) The structural comparison between membrane-associated human carbonic anhydrases provides insights into drug design of selective inhibitors. 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