Role of the bicarbonate-responsive soluble adenylyl cyclase in cholangiocyte apoptosis in primary biliary cholangitis; a new hypothesis

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2018-04, Vol.1864 (4), p.1232-1239
• Main Authors: Chang, Jung-Chin, Go, Simei, Verhoeven, Arthur J., Beuers, Ulrich, Oude Elferink, Ronald P.J.
• Format: Article
• Language: English
• Subjects: Adenylyl Cyclases - metabolism; Anion exchanger 2; Apoptosis; Autoimmune Diseases - etiology; Autoimmune Diseases - pathology; Bicarbonates - metabolism; Bile Acids and Salts - metabolism; Bile Ducts - cytology; Bile Ducts - immunology; Bile Ducts - metabolism; Bile salt; Chloride-Bicarbonate Antiporters - genetics; Chloride-Bicarbonate Antiporters - metabolism; Cholangitis - etiology; Cholangitis - pathology; Epigenesis, Genetic - genetics; Epigenesis, Genetic - immunology; Epithelial Cells - immunology; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Genes, X-Linked - genetics; Humans; MicroRNAs - genetics; MicroRNAs - metabolism; miR-506; Primary biliary cholangitis; Signal Transduction - genetics; Signal Transduction - immunology; Soluble adenylyl cyclase; Up-Regulation
• ISSN: 0925-4439
• DOI: 10.1016/j.bbadis.2017.09.022

Primary biliary cholangitis (PBC) is a chronic fibrosing cholangiopathy characterized by an autoimmune stereotype and defective biliary bicarbonate secretion due to down-regulation of anion exchanger 2 (AE2). Despite the autoimmune features, immunosuppressants are ineffective while two bile acid-based therapies (ursodeoxycholic acid and obeticholic acid) have been shown to improve biochemical and histological features of cholestasis and long-term prognosis. However, the etiology and pathogenesis of PBC is largely unknown. Recently, it has been shown that microRNA-506 (miR-506) on chromosome X is up-regulated in PBC cholangiocytes and suppresses AE2 expression, which sensitizes cholangiocytes to bile salt-induced apoptosis by activating soluble adenylyl cyclase (sAC), an evolutionarily conserved bicarbonate sensor. In this review, we discuss the experimental evidence for the emerging role of the miR-506-AE2-sAC axis in PBC pathogenesis. We further hypothesize that the initial disease trigger induces an X-linked epigenetic change, leading to a female-biased activation of the miR-506-AE2-sAC axis. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni and Peter Jansen. •Literature on the putative disease mechanism of Primary Biliary Cholngitis is reviewed.•Literature on the role of AE2 downregulation in PBC is reviewed.•A novel hypothesis on the role of soluble adenylyl cyclase in the context of AE2 downregulation is launched.