ArticleThe Journal of biological chemistry2011
Hepatic nuclear factor 1alpha (HNF1alpha) dysfunction down-regulates X-box-binding protein 1 (XBP1) and sensitizes beta-cells to endoplasmic reticulum stress.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 23 citations in OpenAlex.
- HNF1α-Q125ter-mediated mitochondrial dysfunction and impaired mitophagy in β-cells.Journal of molecular endocrinology · 2025Article
- Pharmacological and non-pharmacological modulation of endoplasmic reticulum stress in pediatric diabetes.Frontiers in endocrinology · 2025Review
- Endoplasmic reticulum stress in pancreatic β-cell dysfunction: The potential therapeutic role of dietary flavonoids.Current research in pharmacology and drug discovery · 2024Review
- Endoplasmic reticulum stress in pancreatic β-cell dysfunctionality and diabetes mellitus: a promising target for generation of functional hPSC-derived β-cellsFrontiers in endocrinology · 2024Review
- Integrating genetics with single-cell multiomic measurements across disease states identifies mechanisms of beta cell dysfunction in type 2 diabetes.Nature genetics · 2023Article
- HNF1α upregulation and promoter hypermethylation as a cause of glucose dysregulation: a case-control study of Kashmiri MODY population.Journal of endocrinological investigation · 2023Article
- Integration of single-cell multiomic measurements across disease states with genetics identifies mechanisms of beta cell dysfunction in type 2 diabetes.bioRxiv : the preprint server for biology · 2023Article
- Novel Loss-of-Function Variant in HNF1a Induces β-Cell Dysfunction through Endoplasmic Reticulum Stress.International journal of molecular sciences · 2022Article
- XBP1 maintains beta cell identity, represses beta-to-alpha cell transdifferentiation and protects against diabetic beta cell failure during metabolic stress in mice.Diabetologia · 2022Article
- HNF1A Mutations and Beta Cell Dysfunction in Diabetes.International journal of molecular sciences · 2022Review
- The Emerging Roles of Intracellular PCSK9 and Their Implications in Endoplasmic Reticulum Stress and Metabolic Diseases.Metabolites · 2022Review
- Living Dangerously: Protective and Harmful ER Stress Responses in Pancreatic β-Cells.Diabetes · 2021Review
- Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus.Nature reviews. Endocrinology · 2021Review
- Intersection of the ATF6 and XBP1 ER stress pathways in mouse islet cells.The Journal of biological chemistry · 2020Article
- Alpha-synuclein aggregates activate calcium pump SERCA leading to calcium dysregulation.EMBO reports · 2018Article
- Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells.Molecular metabolism · 2017Review
- PAX4 preserves endoplasmic reticulum integrity preventing beta cell degeneration in a mouse model of type 1 diabetes mellitus.Diabetologia · 2016Article
- Involvement of the IRE1α-XBP1 pathway and XBP1s-dependent transcriptional reprogramming in metabolic diseases.DNA and cell biology · 2015Review
- Activation of the unfolded protein response pathway causes ceramide accumulation in yeast and INS-1E insulinoma cells.Journal of lipid research · 2012Article
Corrections and comments
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Authors and funding
10 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Correct endoplasmic reticulum (ER) function is critical for the health of secretory cells, such as the pancreatic β-cell, and ER stress is often a contributory factor to β-cell death in type 2 diabetes. We have used an insulin-secreting cell line with inducible expression of dominant negative (DN) HNF1α, a transcription factor vital for correct β-cell development and function, to show that HNF1α is required for Xbp1 transcription and maintenance of the normal ER stress response. DN HNF1α expression sensitizes the β-cell to ER stress by directly down-regulating Xbp1 transcription, whereas Atf6 is unaffected. Furthermore, DN HNF1α alters calcium homeostasis, resulting in elevated cytoplasmic calcium and increased store-operated calcium entry, whereas mitochondrial calcium uptake is normal. Loss of function of XBP1 is toxic to the β-cell and decreases production of the ER chaperone BiP, even in the absence of ER stress. DN HNF1α-induced sensitivity to cyclopiazonic acid can be partially rescued with the chemical chaperone tauroursodeoxycholate. Rat insulin 2 promoter-DN HNF1α mouse islets express lower levels of BiP mRNA, synthesize less insulin, and are sensitized to ER stress relative to matched control mouse islets, suggesting that this mechanism is also operating in vivo.
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