Inhibition of Foxo1 Protects Pancreatic Islet β-Cells Against Fatty Acid and Endoplasmic Reticulum Stress–Induced Apoptosis
| Autor: | Sara C. Martinez, Ernesto Bernal-Mizrachi, Corentin Cras-Méneur, M. Alan Permutt, Nada A. Abumrad, Katsuya Tanabe |
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| Rok vydání: | 2008 |
| Předmět: |
Male
endocrine system medicine.medical_specialty Programmed cell death Endocrinology Diabetes and Metabolism Palmitic Acid Apoptosis Mice Transgenic FOXO1 Fatty Acids Nonesterified Biology Endoplasmic Reticulum Mice Genes Reporter Cell Line Tumor Insulin-Secreting Cells Internal medicine Internal Medicine medicine Animals Protein kinase B chemistry.chemical_classification Cell Death Forkhead Box Protein O1 Endoplasmic reticulum Fatty acid Forkhead Transcription Factors Cell biology Mice Inbred C57BL Insulin receptor Endocrinology chemistry biology.protein Unfolded protein response Insulinoma Stress Mechanical Signal transduction Oleic Acid Plasmids Propidium Signal Transduction |
| Zdroj: | Diabetes. 57:846-859 |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | OBJECTIVE—β-Cells are particularly susceptible to fatty acid–induced apoptosis associated with decreased insulin receptor/phosphatidylinositol-3 kinase/Akt signaling and the activation of stress kinases. We examined the mechanism of fatty acid–induced apoptosis of mouse β-cells especially as related to the role played by endoplasmic reticulum (ER) stress–induced Foxo1 activation and whether decreasing Foxo1 activity could enhance cell survival.RESEARCH DESIGN AND METHODS—Mouse insulinoma (MIN6) cells were administered with fatty acids, and the role of Foxo1 in mediating effects on signaling pathways and apoptosis was examined by measuring Foxo1 activity and using dominant-negative Foxo1.RESULTS—Increasing fatty acid concentrations (100–400 μmol/l palmitate or oleate) led to early Jun NH2-terminal kinase (JNK) activation that preceded induction of ER stress markers and apoptosis. Foxo1 activity was increased with fatty acid administration and by pharmacological inducers of ER stress, and this increase was prevented by JNK inhibition. Fatty acids induced nuclear localization of Foxo1 at 4 h when Akt activity was increased, indicating that FoxO1 activation was not mediated by JNK inhibition of Akt. In contrast, fatty acid administration for 24 h was associated with decreased insulin signaling. A dominant-negative Foxo1 adenovirus (Adv-DNFoxo) conferred cells with protection from ER stress and fatty acid–mediated apoptosis. Microarray analysis revealed that fatty acid induction of gene expression was in most cases reversed by Adv-DNFoxo, including the proapoptotic transcription factor CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein).CONCLUSIONS—Early induction of JNK and Foxo1 activation plays an important role in fatty acid–induced apoptosis. Expressing a dominant-negative allele of Foxo1 reduces expression of apoptotic and ER stress markers and promotes β-cell survival from fatty acid and ER stress, identifying a potential therapeutic target for preserving β-cells in type 2 diabetes. |
| Databáze: | OpenAIRE |
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