title: Methyl-deficient diet promotes colitis and SIRT1-mediated endoplasmic reticulum stress.
abstract: 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.
  
  
  OBJECTIVE
  We investigated whether the influence of MDD on colitis resulted from an ER stress response triggered by decreased SIRT1 expression.
  
  
  METHODS
  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.
authors.affiliation: INSERM U954, Faculté de Médecine, Nutrition Génétique et exposition aux risques environnementaux, Université de Lorraine 54 511, Vandœuvre-Lès-Nancy cedex, France.
authors.forename: Hassan
authors.initials: H
authors.lastname: Melhem
authors.affiliation: INSERM U954, Faculté de Médecine, Nutrition Génétique et exposition aux risques environnementaux, Université de Lorraine 54 511, Vandœuvre-Lès-Nancy cedex, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Hansmannel
authors.affiliation: INSERM U954, Faculté de Médecine, Nutrition Génétique et exposition aux risques environnementaux, Université de Lorraine 54 511, Vandœuvre-Lès-Nancy cedex, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Bressenot
authors.affiliation: INSERM U954, Faculté de Médecine, Nutrition Génétique et exposition aux risques environnementaux, Université de Lorraine 54 511, Vandœuvre-Lès-Nancy cedex, France.
authors.forename: Syue-Fang
authors.initials: SF
authors.lastname: Battaglia-Hsu
authors.affiliation: INSERM U954, Faculté de Médecine, Nutrition Génétique et exposition aux risques environnementaux, Université de Lorraine 54 511, Vandœuvre-Lès-Nancy cedex, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Billioud
authors.affiliation: INSERM U954, Faculté de Médecine, Nutrition Génétique et exposition aux risques environnementaux, Université de Lorraine 54 511, Vandœuvre-Lès-Nancy cedex, France.
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Alberto
authors.affiliation: INSERM U954, Faculté de Médecine, Nutrition Génétique et exposition aux risques environnementaux, Université de Lorraine 54 511, Vandœuvre-Lès-Nancy cedex, France.
authors.forename: Jean Louis
authors.initials: JL
authors.lastname: Gueant
authors.affiliation: INSERM U954, Faculté de Médecine, Nutrition Génétique et exposition aux risques environnementaux, Université de Lorraine 54 511, Vandœuvre-Lès-Nancy cedex, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Peyrin-Biroulet
mesh_terms: D000818:Animals; D001706:Biopsy; D015153:Blotting, Western; D018938:Caco-2 Cells; D002478:Cells, Cultured; D002796:Choline Deficiency; D003092:Colitis / Q000139:chemically induced*; D004268:DNA-Binding Proteins; D016264:Dextran Sulfate / Q000494:pharmacology; D004032:Diet; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D005494:Folic Acid Deficiency; D006801:Humans; D007124:Immunoenzyme Techniques; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000378:metabolism*; D014157:Transcription Factors; D014162:Transfection; D056811:Unfolded Protein Response; D014806:Vitamin B 12 Deficiency; D019892:eIF-2 Kinase
chemical_list: D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D034741:RNA, Small Interfering; D014157:Transcription Factors; D016264:Dextran Sulfate; D019892:eIF-2 Kinase; D056564:Sirtuin 1
keywords: IBD BASIC RESEARCH