XBP1型
高铁F1
未折叠蛋白反应
内质网
ATF4
热冲击
热冲击系数
西妥因1
热休克蛋白
结肠炎
化学
生物
内分泌学
内科学
癌症研究
细胞生物学
热休克蛋白70
医学
下调和上调
生物化学
核糖核酸
RNA剪接
基因
作者
Hassan Melhem,Franck Hansmannel,Aude Bressenot,Syue-Fang Battaglia-Hsu,Vincent Billioud,Jean‐Marc Alberto,Jean‐Louis Guéant,Laurent Peyrin‐Biroulet
出处
期刊:Gut
[BMJ]
日期:2015-01-20
卷期号:65 (4): 595-606
被引量:59
标识
DOI:10.1136/gutjnl-2014-307030
摘要
Background
Methyl donor deficiency (MDD) aggravates experimental colitis in rats and increases endoplasmic reticulum (ER) stress through decreased sirtuin 1 (SIRT1) in neuronal cells and myocardium. ER stress plays a key role in IBD pathogenesis. Aim
We investigated whether the influence of MDD on colitis resulted from an ER stress response triggered by decreased SIRT1 expression. Design
The unfolded protein response (UPR), chaperones proteins, heat shock factor protein 1 (HSF1) and SIRT1 were examined in rats with MDD and dextran sulfate sodium (DSS)-induced colitis in a Caco-2 cell model with stable expression of transcobalamin–oleosin (TO) chimera, which impairs cellular availability of vitamin B12, and in IBD. The effects of SIRT1 activation were studied both in vitro and in vivo. Results
MDD aggravated DSS-induced colitis clinically, endoscopically and histologically. MDD activated ER stress pathways, with increased phosphorylate-PKR-like ER kinase, P-eiF-2α, P-IRE-1α, activating transcription factor (ATF)6, XBP1-S protein and ATF4 mRNA expression levels in rats. This was accompanied by reduced SIRT1 expression level and greater acetylation of HSF1, in relation with a dramatic decrease of chaperones (binding immunoglobulin protein (BIP), heat shock protein (HSP)27 and HSP90). Adding either vitamin B12, S-adenosylmethionine or an SIRT1 activator (SRT1720) reduced the UPR in vitro. In rats, SIRT1 activation by SRT1720 prevented colitis by reducing HSF1 acetylation and increasing expression of BIP, HSP27 and HSP90. Immunohistochemistry showed impaired expression of SIRT1 in the colonic epithelium of patients with IBD. Conclusions
SIRT1 is a master regulator of ER stress and severity of experimental colitis in case of MDD. It could deserve further interest as a therapeutic target of IBD.
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