Acute hypoxia induces apoptosis of pancreatic β-cell by activation of the unfolded protein response and upregulation of CHOP
Open accessAbstract
The success of pancreatic β-cells transplantation to treat type 1 diabetes has been hindered by massive β-cell dysfunction and loss of β-cells that follows the procedure. Hypoxia-mediated cell death has been considered one of the main difficulties that must be overcome for transplantation to be regarded as a reliable therapy. Here we have investigated the mechanisms underlying β-cell death in response to hypoxia (1% O(2)). Our studies show that mouse insulinoma cell line 6 (Min6) cells undergo apoptosis with caspase-3 activation occurring as early as 2 h following exposure to hypoxia. Hypoxia induces endoplasmic reticulum stress in Min6 cells leading to activation of the three branches of the unfolded protein response pathway. In response to hypoxia the pro-apoptotic transcription factor C/EBP homologous protein (CHOP) is upregulated. The important role of CHOP in the apoptotic process was highlighted by the rescue of Min6 cells from hypoxia-mediated apoptosis observed in CHOP-knockdown cells. Culturing isolated pancreatic mouse islets at normoxia showed intracellular hypoxia with accumulation of hypoxia-inducible factor-1α and upregulation of CHOP, the latter one occurring as early as 4 h after isolation. Finally, we observed that pancreatic islets of type 2 db/db diabetic mice were more hypoxic than their counterpart in normoglycemic animals. This finding indicates that hypoxia-mediated apoptosis may occur in type 2 diabetes.
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HIF-dependent metabolic reprogramming and redox dysregulation exacerbate ER stress, linking hypoxic signaling to UPR activation, particularly through the IRE1α-XBP1 axis.
“Moreover, HIF dependent metabolic reprogramming and redox dysregulation exacerbate endoplasmic reticulum (ER) stress, linking hypoxic signaling to activation of the unfolded protein response (UPR), particularly through the IRE1α–XBP1 axis [[241], [242], [243], [244]].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [241]
The Results section ('Hypoxia activates the UPR in the pancreatic β-cell line Min6'; page not provided) confirms that hypoxia activates the IRE-1/XBP-1 branch. But the paper describes the hypoxic response as HIF-1α-independent, and Results ('Regulation of CHOP by hypoxia in Min6'; page not provided) reports that silencing HIF-1α did not affect hypoxia-induced CHOP expression. It does not establish the claimed causal link from HIF-dependent metabolic reprogramming or redox dysregulation to ER stress. (LLM, conf=0.86)
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Cites
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“Moreover, HIF dependent metabolic reprogramming and redox dysregulation exacerbate endoplasmic reticulum (ER) stress, linking hypoxic signaling to activation of the unfolded protein response (UPR), particularly through the IRE1 α – XBP1 axis [241 – 244].”
- Authors
- Zheng, X., Zheng, X., Wang, X., Ma, Z., Gupta Sunkari, V, Botusan, I., Takeda, T., Björklund, A., Inoue, M., Catrina, S.-B., Brismar, K., Poellinger, L., & Pereira, T. S.
- Affiliations
- Karolinska Institutet (SE)
- Osaka International Cancer Institute (JP)
- National University of Singapore (SG)
- Corresponding author
- Pereira, T S
- Venue
- Cell Death & Disease
- Published
- 2012-06-14
- Volume
- 3
- Issue
- 6
- Pages
- e322-e322
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC3388238
- OpenAlex
- W2079205627
- Cited by
- 99
- References
- 1
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 7 · 2023: 4 · 2022: 7 · 2021: 6 · 2020: 8 · 2019: 6 · 2018: 8 · 2017: 12 · 2016: 16 · 2015: 7 · 2014: 7 · 2013: 2 · 2012: 2
- FWCI
- 2.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Cell Death and Disease (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Funders
- Naito Foundation
- European Commission
- Cancerfonden
- Karolinska Institutet
- Vetenskapsrådet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- hypoxia, pancreatic beta cells, apoptosis, unfolded protein response, CHOP, endoplasmic reticulum stress, caspase-3, pancreatic islets, hypoxia-inducible factor-1α, type 1 diabetes, type 2 diabetes, db/db mice, islet transplantation
- MeSH terms
- Animals, Female, Insulinoma, Male, Mice, Inbred C57BL, Mice, Transgenic, Transcriptional Activation, Cell Hypoxia, Up-Regulation, Apoptosis, Cell Line, Tumor, Insulin-Secreting Cells, Mice, Transcription Factor CHOP, Unfolded Protein Response
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