title: CHOP Contributes to, But Is Not the Only Mediator of, IAPP Induced β-Cell Apoptosis.
abstract: The islet in type 2 diabetes is characterized by β-cell loss, increased β-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 β-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 β-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 β-cell mass and decreased β-cell apoptosis. Deletion of CHOP attenuates dysfunction of the autophagy/lysosomal pathway in β-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 β-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.
authors.affiliation: Larry L. Hillblom Islet Research Center, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7073.
authors.forename: T
authors.initials: T
authors.lastname: Gurlo
authors.affiliation: Larry L. Hillblom Islet Research Center, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7073.
authors.forename: J F
authors.initials: JF
authors.lastname: Rivera
authors.affiliation: Larry L. Hillblom Islet Research Center, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7073.
authors.forename: A E
authors.initials: AE
authors.lastname: Butler
authors.affiliation: Larry L. Hillblom Islet Research Center, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7073.
authors.forename: M
authors.initials: M
authors.lastname: Cory
authors.affiliation: Larry L. Hillblom Islet Research Center, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7073.
authors.forename: J
authors.initials: J
authors.lastname: Hoang
authors.affiliation: Larry L. Hillblom Islet Research Center, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7073.
authors.forename: S
authors.initials: S
authors.lastname: Costes
authors.affiliation: Larry L. Hillblom Islet Research Center, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7073.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Butler
mesh_terms: D000818:Animals; D017209:Apoptosis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D058228:Islet Amyloid Polypeptide / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism
chemical_list: C497250:Ddit3 protein, mouse; D058228:Islet Amyloid Polypeptide; D051742:Transcription Factor CHOP