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Inhibition of Foxo1 Protects Pancreatic Islet ®-Cells Against Fatty Acid and ER-Stress Induced Apoptosis

¹ Division of Endocrinology, Metabolism, and Lipid Research,
² Department of Medicine, Division of Nutritional Science, Washington University School of Medicine, St. Louis, MO

Objective: β-cells are particularly susceptible to fatty acid (FA) induced apoptosis associated with decreased insulin receptor/PI3-kinase/Akt signaling and the activation of stress kinases. We examined the mechanism of FA induced apoptosis of mouse â-cells especially as related to the role played by ER stress-induced Foxo1 activation and whether decreasing Foxo1 activity could enhance cell survival.

Research Design and Methods: Mouse insulinoma (MIN6) cells were treated with FA 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 FA concentrations (100-400 µM palmitate or oleate) led to early Jun-N-terminal kinase (JNK) activation that preceded induction of ER stress markers and apoptosis. Foxo1 activity was increased with FA treatment and by pharmacologic inducers of ER-stress and this increase was prevented by JNK inhibition. FA induced nuclear localization of Foxo1 at 4 hours when Akt activity was increased indicating that FoxO1 activation was not mediated by JNK inhibition of Akt. In contrast, FA treatment for 24 hours was associated with decreased insulin signaling. A dominant-negative Foxo1 adenovirus (Adv-DNFoxo) conferred cells with protection from ER stress and FA mediated apoptosis. Microarray analysis revealed that FA induction of gene expression was in most cases reversed by Adv-DNFoxo, including the pro-apoptotic transcription factor, CHOP.

Conclusions: Early induction of JNK and Foxo1 activation play an important role in FA-induced apoptosis. Expressing a dominant-negative allele of Foxo1 reduces expression of apoptotic and ER stress markers and promotes β-cell survival from FA and ER-stress, identifying a potential therapeutic target for preserving β-cells in type 2 diabetes.

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