FTO OVEREXPRESSION PROTECTS PANCREATIC β-CELLS FROM PALMITATE-INDUCED APOPTOSIS BY PREVENTING ACTIVATION OF THE UNFOLDED PROTEIN RESPONSE

Background. Saturated free fatty acids, such as palmitate, can cause pancreatic beta-cell apoptosis. Although the toxicity of palmitate could be mediated partly through endoplasmic reticulum (ER) stress, the mechanism by which fatty acid over-accumulation led to lipoapoptosis in beta-cells has not been fully understood. Recently, the fat mass and obesity associated (FTO) gene is proved to be related to obesity and type 2 diabetes, but its function in beta-cells remains largely unknown. Whether or not FTO could counteract palmitate induced beta-cell apoptosis remains to be investigated. Methods. INS-I cells were infected with FTO expression adenovirus and incubated with palmitate. Then, viability and induction of apoptosis were measured by MTT assay and Hoechst-staining, respectively. Western blot analyses were performed for unfolded protein response specific proteins and mRNA expression of target molecules was determined by real time-PCR. Results. Palmitate incubation led to beta-cell apoptosis, whereas adenovirus-mediated FTO overexpression significantly ameliorated the effect of palmitate. Increased activation of X-box binding protein I (Xbp 1) mRNA and phosphorylation of eIF2 alpha were also observed after palmitate treatment, whereas FTO overexpression significantly ameliorated the effect of palmitate. The proapoptotic transcription factor CHOP was significantly enhanced by palmitate incubation. In contrast, in accordance with sustained cell survival, FTO overexpression resulted in notably decreased CHOP levels. Interestingly, mRNA expression of the chaperones Pdi, Calnexin and Grp94 was not altered by palmitate treatment, while FTO overexpression notably increased the expression of Bip. Conclusion. Our data showed that FTO overexpression could protect beta-cells from palmitate-induced apoptosis partly through suppression of ER stress.