CHOP deletion does not impact the development of diabetes but suppresses the early production of insulin autoantibody in the NOD mouse

Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Japan.
Apoptosis (Impact Factor: 3.69). 04/2011; 16(4):438-48. DOI: 10.1007/s10495-011-0576-2
Source: PubMed


C/EBP homologous protein (CHOP) has been proposed as a key transcription factor for endoplasmic reticulum (ER) stress-mediated β-cell death induced by inflammatory cytokines in vitro. However, the contribution of CHOP induction to the pathogenesis of type 1 diabetes is not yet clear. To evaluate the relevance of CHOP in the pathogenesis of type 1 diabetes in vivo, we generated CHOP-deficient non-obese diabetic (NOD.Chop
−/−) mice. CHOP deficiency did not affect the development of insulitis and diabetes and apoptosis in β-cells. Interestingly, NOD.Chop
−/− mice exhibited a delayed appearance of insulin autoantibodies compared to wild-type (wt) mice. Adoptive transfer with the diabetogenic, whole or CD8+-depleted splenocytes induced β-cell apoptosis and the rapid onset of diabetes in the irradiated NOD.Chop
−/− recipients with similar kinetics as in wt mice. Expression of ER stress-associated genes was not significantly up-regulated in the islets from NOD.Chop
−/− compared to those from wt mice or NOD-scid mice. These findings suggest that CHOP expression is independent of the development of insulitis and diabetes but might affect the early production of insulin autoantibodies in the NOD mouse.

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Available from: Seiichi Oyadomari
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    • "Moreover, islets from these mice showed resistance to NO, a chemical agent implicated in β cells disruption in type 1 diabetes [96]. In contrast, CHOP deficiency in a genetic background of nonobese diabetic mice (NOD-Chop−/−) did not affect the development of insulitis, diabetes, and β cells apoptosis [97]. Interestingly, CHOP knockout mice on a C57BL/6 background showed a different phenotype, with abdominal obesity and hepatic steatosis, while preserving normal glucose tolerance and insulin sensitivity [98]. "
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    • "Our study does not address whether this reduction in β-cell mass in prediabetic NOD mice is a direct consequence of ER stress. Interestingly, a recent study by Satoh et al. (14) showed that global Chop deletion on the NOD background did not protect against β-cell loss or diabetes development. Moreover, studies using isolated rodent and human islets suggest that ER stress may not directly contribute to β-cell death, but rather to insulin secretory defects (11). "
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