title: microRNA-199a-5p protects hepatocytes from bile acid-induced sustained endoplasmic reticulum stress.
abstract: Sustained endoplasmic reticulum (ER) stress has been linked to cell death and the pathogenesis of many liver diseases, including toxic liver, cholestasis, and infectious liver disease. The cellular pathways that attenuate hepatic ER stress have been the focus of many recent studies, but the role of microRNAs (miRNA) in this process remains unknown. Here, we report that one of the most abundant miRNAs in hepatocytes, miR-199a-5p, was elevated in both bile acid- and thapsigargin (TG)-stimulated cultured hepatocytes, as well as in the liver of bile duct-ligated mice. We identify the misfolded protein chaperone GRP78, as well as the unfolded protein response transducers endoplasmic reticulum to nucleus signaling 1 and activating transcription factor 6 as direct targets of miR-199a-5p, and show that endogenous miR-199a-5p represses the 3' untranslated regions (UTRs) of their mRNAs. Through gain-of-function and loss of function approaches, we demonstrate that the elevated miR-199-5p disrupts sustained ER stress and prevents hepatocytes from undergoing bile acid- or TG-induced cell death. Furthermore, we reveal that the transcription factor AP-1 is a strong positive regulator of miR-199a-5p. In brief, our study demonstrates that AP-1/miR-199a-5p and ER stress mediators form a feedback loop, which shields hepatocytes from sustained ER stress and protects the liver from injury. On the basis of these findings, we also suggest that the miRNA miR-199a-5p is a potential target for clinical approaches aiming to protect hepatocytes in liver disease.
authors.affiliation: The Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: B-H
authors.initials: BH
authors.lastname: Dai
authors.forename: L
authors.initials: L
authors.lastname: Geng
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: C-J
authors.initials: CJ
authors.lastname: Sui
authors.forename: F
authors.initials: F
authors.lastname: Xie
authors.forename: R-X
authors.initials: RX
authors.lastname: Shen
authors.forename: W-F
authors.initials: WF
authors.lastname: Shen
authors.forename: J-M
authors.initials: JM
authors.lastname: Yang
mesh_terms: D020413:3' Untranslated Regions; D051702:Activating Transcription Factor 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043244:Ribonuclease III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D001647:Bile Acids and Salts; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D035683:MicroRNAs; C534780:Mirn199 microRNA, mouse; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D019284:Thapsigargin; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases