microRNA-199a-5p protects hepatocytes from bile acid-induced sustained endoplasmic reticulum stress.
microRNA-199a-5p protects hepatocytes from bile acid-induced sustained endoplasmic reticulum stress.
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microRNA-199a-5p 保护肝细胞免受胆汁酸诱导的持续内质网应激
DOI：
10.1038/cddis.2013.134
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发表时间：
2013-04-18
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
持续的内质网（ER）应激与细胞死亡和许多肝脏疾病的发病机制有关，包括中毒性肝，胆汁淤积和感染性肝病。减轻肝脏内质网应激的细胞通路是近年来许多研究的焦点，但microRNA（miRNA）在这一过程中的作用仍不清楚。在这里，我们报告了肝细胞中最丰富的miRNAs之一，miR-199 a-5 p，在胆汁酸和毒胡萝卜素（TG）刺激的培养肝细胞中升高，以及在胆管结扎小鼠的肝脏中。我们鉴定了错误折叠的蛋白伴侣GRP 78以及未折叠的蛋白反应转导物内质网对核信号传导1和激活转录因子6作为miR-199 a-5 p的直接靶点，并表明内源性miR-199 a-5 p抑制其mRNA的3′非翻译区（UTR）。通过功能获得和功能丧失的方法，我们证明了升高的miR-199- 5 p破坏了持续的ER应激，并阻止肝细胞经历胆汁酸或TG诱导的细胞死亡。此外，我们发现转录因子AP-1是miR-199 a-5 p的强正调控因子。简而言之，我们的研究表明AP-1/miR-199 a-5 p和ER应激介质形成反馈回路，其保护肝细胞免受持续的ER应激并保护肝脏免受损伤。基于这些发现，我们还认为miRNA miR-199 a-5 p是旨在保护肝病肝细胞的临床方法的潜在靶点。
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.
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DOI：
10.1074/jbc.m111.228817
发表时间：
2011-10-21
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Birkenfeld AL;Lee HY;Majumdar S;Jurczak MJ;Camporez JP;Jornayvaz FR;Frederick DW;Guigni B;Kahn M;Zhang D;Weismann D;Arafat AM;Pfeiffer AF;Lieske S;Oyadomari S;Ron D;Samuel VT;Shulman GI
通讯作者：
Shulman GI
影响因子：
13.5
作者：
Messner, Donald J;Kowdley, Kris V
通讯作者：
Kowdley, Kris V
DOI：
10.1034/j.1600-0676.2002.00002.x
发表时间：
2002-04-01
期刊：
LIVER
影响因子：
--
作者：
Hofmann, AF
通讯作者：
Hofmann, AF
影响因子：
13.3
作者：
Crighton, Diane;Wilkinson, Simon;Ryan, Kevin M.
通讯作者：
Ryan, Kevin M.
影响因子：
25.7
作者：
Malhi, Harmeet;Kaufman, Randal J.
通讯作者：
Kaufman, Randal J.