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

Abstract

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.

• Authors: Jung-Chin Chang, Simei Go, Arthur J Verhoeven, Ulrich Beuers, Ronald P J Oude Elferink
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1864 Issue 4 Pt B Pg. 1232-1239 (04 2018) ISSN: 0925-4439 [Print] Netherlands
• PMID: 28962898 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Bicarbonates
• Bile Acids and Salts
• Chloride-Bicarbonate Antiporters
• MIRN506 microRNA, human
• MicroRNAs
• SLC4A2 protein, human
• ADCY10 protein, human
• Adenylyl Cyclases

Topics

• Adenylyl Cyclases (metabolism)
• Apoptosis
• Autoimmune Diseases (etiology, pathology)
• Bicarbonates (metabolism)
• Bile Acids and Salts (metabolism)
• Bile Ducts (cytology, immunology, metabolism)
• Chloride-Bicarbonate Antiporters (genetics, metabolism)
• Cholangitis (etiology, pathology)
• Epigenesis, Genetic (genetics, immunology)
• Epithelial Cells (immunology, metabolism, pathology)
• Female
• Genes, X-Linked (genetics)
• Humans
• MicroRNAs (genetics, metabolism)
• Signal Transduction (genetics, immunology)
• Up-Regulation