ArticleDiabetologia2016
Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells.
Article in Diabetologia, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 77 citations in OpenAlex.
- Unfolded Protein Response Pathways in Cancer: Mechanisms, Tumor Biology and Therapeutic Opportunities.Molecular diagnosis & therapy · 2026Review
- Global stabilization of the mitochondrial proteome is associated with extreme anoxia tolerance in Austrofundulus limnaeus WS40NE cells.BMC biology · 2026Article
- Divergent cell-type specific hypoxia responses in human stem cell-derived and primary islets.Scientific reports · 2026Article
- Mechanical Cues Regulate Cargo Sorting and Export at the Golgi.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Review
- The lactate sensor NDRG3 decelerates ER-to-Golgi transport through interaction with the long isoform of syntaxin-5.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Genomic differentiation between wild and domesticated populations of large yellow croaker (Larimichthys crocea): environmental impacts.BMC genomics · 2025Article
- Rescuing vascular dysfunction in dorsal pancreatic arteries prevents tacrolimus-induced glucose metabolism disorder in mice.Molecular medicine (Cambridge, Mass.) · 2025Article
- Improving cellular fitness of human stem cell-derived islets under hypoxia.Nature communications · 2025Article
- Gut microbiota modulate intestinal inflammation by endoplasmic reticulum stress-autophagy-cell death signaling axis.Journal of animal science and biotechnology · 2025Review
- Article
- Golgi condensation causes intestinal lipid accumulation through HIF-1α-mediated GM130 ubiquitination by NEDD4.Experimental & molecular medicine · 2025Article
- β-Cell Deletion of Hypoxia-Inducible Factor 1α (HIF-1α) Increases Pancreatic β-Cell Susceptibility to Streptozotocin.International journal of molecular sciences · 2024Article
- Harmine and exendin-4 combination therapy safely expands human β cell mass in vivo in a mouse xenograft system.Science translational medicine · 2024Article
- Article
- Roles of β-Cell Hypoxia in the Progression of Type 2 Diabetes.International journal of molecular sciences · 2024Review
- Topical hADSCs-HA Gel Promotes Skin Regeneration and Angiogenesis in Pressure Ulcers by Paracrine Activating PPARβ/δ Pathway.Drug design, development and therapy · 2024Article
- Adipose Tissue Hypoxia in Obesity: Clinical Reappraisal of Hypoxia Hypothesis.Advances in experimental medicine and biology · 2024Review
- The Unfolded Protein Response: A Double-Edged Sword for Brain Health.Antioxidants (Basel, Switzerland) · 2023Review
- Review
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aims/hypothesisHypoxia may contribute to beta cell failure in type 2 diabetes and islet transplantation. The adaptive unfolded protein response (UPR) is required for endoplasmic reticulum (ER) homeostasis. Here we investigated whether or not hypoxia regulates the UPR in beta cells and the role the adaptive UPR plays during hypoxic stress.
methodsMouse islets and MIN6 cells were exposed to various oxygen (O2) tensions. DNA-damage inducible transcript 3 (DDIT3), hypoxia-inducible transcription factor (HIF)1α and HSPA5 were knocked down using small interfering (si)RNA; Hspa5 was also overexpressed. db/db mice were used.
resultsHypoxia-response genes were upregulated in vivo in the islets of diabetic, but not prediabetic, db/db mice. In isolated mouse islets and MIN6 cells, O2 deprivation (1-5% vs 20%; 4-24 h) markedly reduced the expression of adaptive UPR genes, including Hspa5, Hsp90b1, Fkbp11 and spliced Xbp1. Coatomer protein complex genes (Copa, Cope, Copg [also known as Copg1], Copz1 and Copz2) and ER-to-Golgi protein trafficking were also reduced, whereas apoptotic genes (Ddit3, Atf3 and Trb3 [also known as Trib3]), c-Jun N-terminal kinase (JNK) phosphorylation and cell death were increased. Inhibition of JNK, but not HIF1α, restored adaptive UPR gene expression and ER-to-Golgi protein trafficking while protecting against apoptotic genes and cell death following hypoxia. DDIT3 knockdown delayed the loss of the adaptive UPR and partially protected against hypoxia-induced cell death. The latter response was prevented by HSPA5 knockdown. Finally, Hspa5 overexpression significantly protected against hypoxia-induced cell death. CONCLUSIONS/
interpretationHypoxia inhibits the adaptive UPR in beta cells via JNK and DDIT3 activation, but independently of HIF1α. Downregulation of the adaptive UPR contributes to reduced ER-to-Golgi protein trafficking and increased beta cell death during hypoxic stress.
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