Inhibition of Foxol protects pancreatic islet β-cells against fatty acid and endoplasmic reticulum stress-induced apoptosis

OBJECTIVE - P-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 P-cells especially as related to the role played by endoplasmic reticulum (ER) stress-induced Foxol activation and whether decreasing Foxol activity could enhance cell survival. RESEARCH DESIGN AND METHODS - Mouse insulinoma (MIN6) cells were administered with fatty acids, and the role of Foxol in mediating effects on signaling pathways and apoptosis was examined by measuring Foxol activity and using dominant-negative Foxol. RESULTS - Increasing fatty acid concentrations (100-400 mu mol/l palmitate or oleate) led to early Jun NH2-terminal kinase (JNK) activation that preceded induction of ER stress markers and apoptosis. Foxol 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 Foxol 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 Foxol 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 Foxol activation plays an important role in fatty acid-induced apoptosis. Expressing a dominant-negative allele of Foxol reduces expression of apoptotic and ER stress markers and promotes P-cell survival from fatty acid and ER stress, identifying a potential therapeutic target for preserving P-cells in type 2 diabetes.