Details

Autor(en) / Beteiligte

• Gurlo, T
• Rivera, J F
• Butler, A E
• Cory, M
• Hoang, J
• Costes, S
• Butler, Peter C

Titel

CHOP Contributes to, But Is Not the Only Mediator of, IAPP Induced [beta]-Cell Apoptosis

Ist Teil von

• Molecular endocrinology (Baltimore, Md.), 2016-04, Vol.30 (4), p.446-454

Erscheinungsjahr

2016

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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 super(-/-) 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.