Volume 69, Issue 6, Pages 1371-1383 (December 2018) Primary biliary cholangitis: A tale of epigenetically-induced secretory failure?  Pedro M. Rodrigues, Maria J. Perugorria, Alvaro Santos-Laso, Luis Bujanda, Ulrich Beuers, Jesus M. Banales  Journal of Hepatology  Volume 69, Issue 6, Pages 1371-1383 (December 2018) DOI: 10.1016/j.jhep.2018.08.020 Copyright © 2018 European Association for the Study of the Liver Terms and Conditions

Fig. 1 MiR-506-induced secretory failure in PBC: A new hypothesis for disease pathogenesis. Under physiological conditions, secretin binds to its receptor in cholangiocytes, promoting the cAMP/PKA-dependent exocytosis of vesicles containing the Cl− channel CFTR, AE2 and the water channel AQP1 to the apical membrane of cholangiocytes.147,148 This leads to the Cl− secretion via CFTR and its further exchange with HCO3− through AE2 that creates a luminal osmotic gradient for the movement of water by AQP1, consequently resulting in choleresis.76,79,149–152 Biliary HCO3− secretion induces the alkalinisation and fluidisation of bile and creates a “biliary bicarbonate umbrella” that protects cholangiocytes against the damaging effect of the cytotoxic bile acids secreted through the canalicular BSEP, reducing their protonation status.79,81,82 On the other hand, acetylcholine increases the cytosolic Ca2+ level through an InsP3R3-dependent mechanism, which activates the apical Cl− secretion through TMEM16A and subsequent Cl−/HCO3− exchange via AE2.76,153,154 In PBC, miR-506 is found upregulated in cholangiocytes where it directly targets both AE2 and InsP3R3, resulting in intracellular pH and Ca2+ alterations and impaired biliary bicarbonate secretion that ends in cholestasis.109,110 As a consequence of the decreased biliary bicarbonate secretion, toxic bile acids are able to enter cholangiocytes in an uncontrolled fashion and promote apoptosis. Under these conditions, the mitochondrial energetic metabolism is severely disturbed, ending in decreased ATP production and PDC-E2 overexpression and aberrant localisation, contributing to immune activation.111 Ach, acetylcholine; AE2, Na+-independent Cl−/HCO3− exchanger 2; AQP1, aquaporin 1; BSEP, bile salt export pump; cAMP, cyclic adenosine monophosphate; CFTR, cystic fibrosis transmembrane conductance regulator; ER, endoplasmic reticulum; FXR, farnesoid X receptor; InsP3R3, type III inositol 1,4,5-trisphosphate receptor; PDC-E2, E2 component of the pyruvate dehydrogenase complex; pHi, intracellular pH; TMEM16A, transmembrane member 16A. Journal of Hepatology 2018 69, 1371-1383DOI: (10.1016/j.jhep.2018.08.020) Copyright © 2018 European Association for the Study of the Liver Terms and Conditions