ArticleDiabetologia2021
Saturated fatty acids entrap PDX1 in stress granules and impede islet beta cell function.
Article in Diabetologia, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 32 citations in OpenAlex.
- Proteomic Analysis on Human Islets Suggests Nucleocytoplasmic Transport as a Mechanism of PERK Attenuation Effects in Diabetes.Molecular & cellular proteomics : MCP · 2026Article
- The Welander TIA1 mutation dedifferentiates insulin-producing cells: Reversal by a GLP-1 receptor agonist.The Journal of biological chemistry · 2026Article
- Hepatocyte TIA1 constrains metabolic steatohepatitis by translationally suppressing Srebf1 mRNA in stress granules.Cell death & disease · 2026Article
- Cholesterol-activated stress granules reduce the membrane localization of DRD2 and promote prolactinoma dopamine agonists resistance.Acta neuropathologica communications · 2025Article
- Crosstalk Between Phase-Separated Membraneless Condensates and Membrane-Bound Organelles in Cellular Function and Disease.Advances in experimental medicine and biology · 2025Review
- Spatiotemporal proteomics reveals the biosynthetic lysosomal membrane protein interactome in neurons.Nature communications · 2024Article
- Dysregulated palmitic acid metabolism promotes the formation of renal calcium-oxalate stones through ferroptosis induced by polyunsaturated fatty acids/phosphatidic acid.Cellular and molecular life sciences : CMLS · 2024Article
- Palmitate induces integrated stress response and lipoapoptosis in trophoblasts.Cell death & disease · 2024Article
- Protopanaxadiol ameliorates palmitate-induced lipotoxicity and pancreatic β-cell dysfunction in INS-1 cells.Journal of ginseng research · 2023Article
- Circular RNA circGlis3 protects against islet β-cell dysfunction and apoptosis in obesity.Nature communications · 2023Article
- Liquid-Liquid Phase Separation of Biomacromolecules and Its Roles in Metabolic Diseases.Cells · 2022Review
- Significance of pancreatic duodenal homeobox-1 (BMJ open diabetes research & care · 2022Article
- Review
- The Multifunctional Faces of T-Cell Intracellular Antigen 1 in Health and Disease.International journal of molecular sciences · 2022Review
- Regulation of Pdx1 by oxidative stress and Nrf2 in pancreatic beta-cells.Frontiers in endocrinology · 2022Review
- Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus.Nature reviews. Endocrinology · 2021Review
- Favorable Effects of GLP-1 Receptor Agonist against Pancreatic β-Cell Glucose Toxicity and the Development of Arteriosclerosis: "The Earlier, the Better" in Therapy with Incretin-Based Medicine.International journal of molecular sciences · 2021Review
- OVEREXPRESSION OF PDX-1 GENE INCREASES INS1 GENE mRNA EXPRESSION, NOT INS2 GENE mRNA EXPRESSION, IN INSULINOMA CELL LINE RIN-5F.Acta endocrinologica (Bucharest, Romania : 2005)Article
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aims/hypothesisFailure of pancreatic and duodenal homeobox factor 1 (PDX1) to localise in the nucleus of islet beta cells under high-fat diet (HFD) conditions may be an early functional defect that contributes to beta cell failure in type 2 diabetes; however, the mechanism of PDX1 intracellular mislocalisation is unclear. Stress granules (SGs) are membrane-less cytoplasmic structures formed under stress that impair nucleocytoplasmic transport by sequestering nucleocytoplasmic transport factors and components of the nuclear pore complex. In this study, we investigated the stimulators that trigger SG formation in islet beta cells and the effects of SGs on PDX1 localisation and beta cell function.
methodsThe effect of palmitic acid (PA) on nucleocytoplasmic transport was investigated by using two reporters, S-tdTomato and S-GFP. SG assembly in rat insulinoma cell line INS1 cells, human islets under PA stress, and the pancreas of diet-induced obese mice was analysed using immunofluorescence and immunoblotting. SG protein components were identified through mass spectrometry. SG formation was blocked by specific inhibitors or genetic deletion of essential SG proteins, and then PDX1 localisation and beta cell function were investigated in vitro and in vivo.
resultsWe showed that saturated fatty acids (SFAs) are endogenous stressors that disrupted nucleocytoplasmic transport and stimulated SG formation in pancreatic beta cells. Using mass spectrometry approaches, we revealed that several nucleocytoplasmic transport factors and PDX1 were localised to SGs after SFA treatment, which inhibited glucose-induced insulin secretion. Furthermore, we found that SFAs induced SG formation in a phosphoinositide 3-kinase (PI3K)/eukaryotic translation initiation factor 2α (EIF2α) dependent manner. Disruption of SG assembly by PI3K/EIF2α inhibitors or genetic deletion of T cell restricted intracellular antigen 1 (TIA1) in pancreatic beta cells effectively suppressed PA-induced PDX1 mislocalisation and ameliorated HFD-mediated beta cell dysfunction. CONCLUSIONS/
interpretationOur findings suggest a link between SG formation and beta cell dysfunction in the presence of SFAs. Preventing SG formation may be a potential therapeutic strategy for treating obesity and type 2 diabetes.
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