Methyl-deficient diet promotes colitis and SIRT1-mediated endoplasmic reticulum stress.

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Date publication

janvier 2015

Auteurs

Membres identifiés du Cancéropôle Est :
Pr GUEANT Jean-Louis, Dr BATTAGLIA-HSU Shyue-Fang


Tous les auteurs :
Melhem H, Hansmannel F, Bressenot A, Battaglia-Hsu SF, Billioud V, Alberto JM, Gueant JL, Peyrin-Biroulet L

Résumé

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-2alpha, P-IRE-1alpha, 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.

Référence

Gut. 2015 Jan 20. pii: gutjnl-2014-307030