Fenofibrate attenuates fatty acid-induced islet β-cell dysfunction and apoptosis via inhibiting the NF-κB/MIF dependent inflammatory pathway

Abstract

BackgroundFatty acid-induced lipotoxicity and macrophage migration inhibitory factor (MIF) affect pancreatic β-cell function, and may promote the development of diabetes mellitus. However, the association of lipotoxicity with MIF and the effect of Fenofibrate on β-cell function remain unknown. MethodsLPL+/− mice and MIN6 cells stimulated with palmitic acid (PA) were utilized as models of lipid metabolism disorders. Factors associated with insulin secretion and apoptosis were assessed in the presence or absence of Fenofibrate. The possible mechanisms of lipotoxicity-induced β-cell dysfunction were also explored. ResultsFenofibrate effectively improved lipid accumulation in pancreatic β-cells, increased glucose-stimulated insulin secretion and β-cell mass, and significantly downregulated pro-apoptotic molecules, at the gene and protein levels, both in vivo and in vitro. Additionally, elevated MIF levels in serum from LPL+/− mice and PA-treated MIN6 cells were starkly decreased after Fenofibrate administration. Mechanistic analysis indicated that NF-κB signaling was remarkably triggered, which could further activate MIF transcription. Furthermore, Fenofibrate exerted beneficial effects on fatty acid-induced β-cell dysfunction likely by inhibiting the NF-κB/MIF dependent inflammatory response. ConclusionsFenofibrate ameliorates lipotoxicity-induced β-cell dysfunction and apoptosis by inhibiting the NF-κB/MIF inflammatory pathway. These findings provide novel insights into the treatment of lipotoxicity-induced metabolic disorders.