| First Author | Gurlo T | Year | 2016 |
| Journal | Mol Endocrinol | Volume | 30 |
| Issue | 4 | Pages | 446-54 |
| PubMed ID | 26900721 | Mgi Jnum | J:321105 |
| Mgi Id | MGI:6882756 | Doi | 10.1210/me.2015-1255 |
| Citation | Gurlo T, et al. (2016) CHOP Contributes to, But Is Not the Only Mediator of, IAPP Induced beta-Cell Apoptosis. Mol Endocrinol 30(4):446-54 |
| abstractText | The islet in type 2 diabetes is characterized by beta-cell loss, increased beta-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). When protein misfolding protective mechanisms are overcome, human IAPP (h-IAPP) forms membrane permeant toxic oligomers that induce beta-cell dysfunction and apoptosis. In humans with type 2 diabetes (T2D) and mice transgenic for h-IAPP, endoplasmic reticulum (ER) stress has been inferred from nuclear translocation of CCAAT/enhancer-binding protein homologous protein (CHOP), an established mediator of ER stress. To establish whether h-IAPP toxicity is mediated by ER stress, we evaluated diabetes onset and beta-cell mass in h-IAPP transgenic (h-TG) mice with and without deletion of CHOP in comparison with wild-type controls. Diabetes was delayed in h-TG CHOP(-/-) mice, with relatively preserved beta-cell mass and decreased beta-cell apoptosis. Deletion of CHOP attenuates dysfunction of the autophagy/lysosomal pathway in beta-cells of h-TG mice, uncovering a role for CHOP in mediating h-IAPP-induced dysfunction of autophagy. As deletion of CHOP delayed but did not prevent h-IAPP-induced beta-cell loss and diabetes, we examined CHOP-independent stress pathways. JNK, a target of the IRE-1pTRAF2 complex, and the Bcl-2 family proapoptotic mediator BIM, a target of ATF4, were comparably activated by h-IAPP expression in the presence and absence of CHOP. Therefore, although these studies affirm that CHOP is a mediator of h-IAPP-induced ER stress, it is not the only one. Therefore, suppression of CHOP alone is unlikely to be a durable therapeutic strategy to protect against h-IAPP toxicity because multiple stress pathways are activated. |
