La carence en vitamine B12 induit un stress du réticulum endoplasmique dû à une diminution de la déacétylase SIRT1 et une augmentation de l'acétylation de HSF1

Abstract : Vitamin B12 deficiency is common in elderly population and produces neurodegenerative disorders by elusive mechanisms. B12 is a key determinant for the S-adenosyl methionine-dependent epigenomic regulations. We have established a B12-deficient cell model via the stable expression of transcobalamin-oleosin chimera (TO), which impairs cellular availability of vitamin B12, reduces SAM level and cell proliferation. Since the expression of oleosin transcobalamin chimera (OT) does not modify the phenotype of the transfected cells, these cells serve as control cells. TO cells present a B12-dependant decrease of deacetylase SIRT1 (sirtuin1) and an endoplasmic reticulum stress (ER stress) reflected by the increased expression of ER stress tranducers, decreased chaperon proteins and increased pro-apoptotic markers. We propose that the decreased expression of SIRT1 triggers cell response to nutritional stress through ER stress. This decrease results in a greater acetylation of heat-shock factor protein 1 (HSF1) and thus reducing the expression of heat shock proteins (HSP). Adding B12, SIRT1, or HSF1 activators as well as overexpressing SIRT1 or HSF1 reduce ER stress. In OT cells, thapsigargin treatment or impairing SIRT1 and HSF1 leads to B12-reversible ER stress. Treating OT cells with AdoX, an inhibitor of methyltransferase activities, produces effects similar to those observed in cells with decreased B12 availability. In summary, the impaired cellular availability of vitamin B12 induces ER stress by increasing HSF1 acetylation through a decreased SIRT1 expression and adding vitamin B12 produces neuro-protective effects in cells subjected to prior ER stress. These results suggest evaluating the effects of SIRT1 agonists on cerebral complications due to a B12 deficiency
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Rose Issam Ghemrawi. La carence en vitamine B12 induit un stress du réticulum endoplasmique dû à une diminution de la déacétylase SIRT1 et une augmentation de l'acétylation de HSF1. Médecine humaine et pathologie. Université de Lorraine, 2013. Français. ⟨NNT : 2013LORR0131⟩. ⟨tel-01750124⟩

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