PMID- 23598416
OWN - NLM
STAT- MEDLINE
DCOM- 20131023
LR  - 20211203
IS  - 2041-4889 (Electronic)
VI  - 4
IP  - 4
DP  - 2013 Apr 18
TI  - microRNA-199a-5p protects hepatocytes from bile acid-induced sustained 
      endoplasmic reticulum stress.
PG  - e604
LID - 10.1038/cddis.2013.134 [doi]
AB  - 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.
FAU - Dai, B-H
AU  - Dai BH
AD  - The Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, 
      Second Military Medical University, Shanghai, China.
FAU - Geng, L
AU  - Geng L
FAU - Wang, Y
AU  - Wang Y
FAU - Sui, C-J
AU  - Sui CJ
FAU - Xie, F
AU  - Xie F
FAU - Shen, R-X
AU  - Shen RX
FAU - Shen, W-F
AU  - Shen WF
FAU - Yang, J-M
AU  - Yang JM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130418
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (3' Untranslated Regions)
RN  - 0 (Activating Transcription Factor 6)
RN  - 0 (Atf6 protein, mouse)
RN  - 0 (Bile Acids and Salts)
RN  - 0 (Endoplasmic Reticulum Chaperone BiP)
RN  - 0 (HSPA5 protein, human)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Hspa5 protein, mouse)
RN  - 0 (MicroRNAs)
RN  - 0 (Mirn199 microRNA, mouse)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factor AP-1)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 2.7.11.1 (Ern1 protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 3.1.- (Endoribonucleases)
RN  - EC 3.1.26.3 (Dicer1 protein, mouse)
RN  - EC 3.1.26.3 (Ribonuclease III)
RN  - EC 3.6.4.13 (DEAD-box RNA Helicases)
SB  - IM
MH  - 3' Untranslated Regions
MH  - Activating Transcription Factor 6/antagonists & inhibitors/genetics/metabolism
MH  - Animals
MH  - Apoptosis
MH  - Bile Acids and Salts/*pharmacology
MH  - Cells, Cultured
MH  - DEAD-box RNA Helicases/antagonists & inhibitors/genetics/metabolism
MH  - Endoplasmic Reticulum Chaperone BiP
MH  - Endoplasmic Reticulum Stress/*drug effects
MH  - Endoribonucleases/antagonists & inhibitors/genetics/metabolism
MH  - Female
MH  - HEK293 Cells
MH  - Heat-Shock Proteins/genetics/metabolism
MH  - Hepatocytes/drug effects/*metabolism
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - MicroRNAs/*metabolism
MH  - Protein Serine-Threonine Kinases/antagonists & inhibitors/genetics/metabolism
MH  - RNA, Messenger/metabolism
MH  - Ribonuclease III/antagonists & inhibitors/genetics/metabolism
MH  - Thapsigargin/pharmacology
MH  - Transcription Factor AP-1/metabolism
PMC - PMC3668635
EDAT- 2013/04/20 06:00
MHDA- 2013/10/24 06:00
PMCR- 2013/04/01
CRDT- 2013/04/20 06:00
PHST- 2013/04/20 06:00 [entrez]
PHST- 2013/04/20 06:00 [pubmed]
PHST- 2013/10/24 06:00 [medline]
PHST- 2013/04/01 00:00 [pmc-release]
AID - cddis2013134 [pii]
AID - 10.1038/cddis.2013.134 [doi]
PST - epublish
SO  - Cell Death Dis. 2013 Apr 18;4(4):e604. doi: 10.1038/cddis.2013.134.