{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T17:19:51Z","timestamp":1775409591880,"version":"3.50.1"},"reference-count":50,"publisher":"S. Karger AG","issue":"3","license":[{"start":{"date-parts":[[2017,1,1]],"date-time":"2017-01-01T00:00:00Z","timestamp":1483228800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2017,1,1]],"date-time":"2017-01-01T00:00:00Z","timestamp":1483228800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Dig Dis"],"published-print":{"date-parts":[[2017]]},"abstract":"<jats:p>&lt;b&gt;&lt;i&gt;Background:&lt;\/i&gt;&lt;\/b&gt; 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. &lt;b&gt;&lt;i&gt;Key Messages:&lt;\/i&gt;&lt;\/b&gt; 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 Ca&lt;sup&gt;2+&lt;\/sup&gt; 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. &lt;b&gt;&lt;i&gt;Conclusions:&lt;\/i&gt;&lt;\/b&gt; 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.<\/jats:p>","DOI":"10.1159\/000450914","type":"journal-article","created":{"date-parts":[[2017,3,1]],"date-time":"2017-03-01T22:01:32Z","timestamp":1488405692000},"page":"217-223","source":"Crossref","is-referenced-by-count":8,"title":["The Emerging Role of Soluble Adenylyl Cyclase in Primary Biliary Cholangitis"],"prefix":"10.1159","volume":"35","author":[{"given":"Jung-Chin","family":"Chang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Beuers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald P.J.","family":"Oude 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