microRNA-199a-5p protects hepatocytes from bile acid-induced sustained endoplasmic reticulum stress

• Published in: Cell death & disease Vol. 4; no. 4; p. e604
• Main Authors: Dai, B-H, Geng, L, Wang, Y, Sui, C-J, Xie, F, Shen, R-X, Shen, W-F, Yang, J-M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2013; Springer Nature B.V; Nature Publishing Group
• Subjects: 3' Untranslated Regions; 631/337/384/331; 631/80/642/1463; 631/80/82; 692/698/2741/288/2032; Activating Transcription Factor 6 - antagonists & inhibitors; Activating Transcription Factor 6 - genetics; Activating Transcription Factor 6 - metabolism; Animals; Antibodies; Apoptosis; Bile Acids and Salts - pharmacology; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cells, Cultured; DEAD-box RNA Helicases - antagonists & inhibitors; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Endoplasmic Reticulum Stress - drug effects; Endoribonucleases - antagonists & inhibitors; Endoribonucleases - genetics; Endoribonucleases - metabolism; Female; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; HEK293 Cells; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; Immunology; Life Sciences; Mice; Mice, Inbred C57BL; MicroRNAs - metabolism; Original; original-article; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Ribonuclease III - antagonists & inhibitors; Ribonuclease III - genetics; Ribonuclease III - metabolism; RNA, Messenger - metabolism; Thapsigargin - pharmacology; Transcription Factor AP-1 - metabolism; GRP78; miR-199a-5p; bile acid; ATF6; endoplasmic reticulum stress
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2013.134

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.