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.

Primary Biliary Cholangitis and Primary Sclerosing Cholangitis: Current Knowledge of Pathogenesis and Therapeutics

“…In addition to several studies indicating that AE2 was reduced in PBC, a recent study reported that downregulation of AE2 may sensitize BECs to apoptotic insults activating soluble adenylyl cyclase (sAC) [ 39 ]. sAC, an evolutionarily conserved bicarbonate sensor, plays a key role in regulating bile salt-induced apoptosis [ 42 ]. Reduced AE2 expression leads to a decrease in the bicarbonate secretion and bicarbonate accumulation in the cells.…”

Pharmacological modulation of the CO2/HCO3−/pH-, calcium-, and ATP-sensing soluble adenylyl cyclase

“…sAC has been shown to play a role in a number of physiological processes (Buffone, Wertheimer, Visconti, & Krapf, 2014; Chang, Beuers, & Oude Elferink, 2017; Desman, Waintraub, & Zippin, 2014; Ladilov & Appukuttan, 2014; Lee, Marmorstein, & Marmorstein, 2014; Levin & Buck, 2015; Muller, 2016; Schmid, Meili, & Salathe, 2014; Shim, Kim, & Ju, 2017; Stiles, Kapiloff, & Goldberg, 2014; Valsecchi, Konrad, & Manfredi, 2014). A number of sAC’s physiological roles have been identified genetically, via phenotypes observed in genetically engineered mice (Table 2).…”

Hepatobiliary acid-base homeostasis: Insights from analogous secretory epithelia

“…Bile acid exposure activates sAC causing downstream cytochrome c release and apoptosis, which can be prevented by sAC inhibition. These findings provide insight into the promising role of sAC in the pathogenesis of PBC [124].…”