Inhibition of Foxo1 mediates protective effects of ghrelin against lipotoxicity in MIN6 pancreatic beta-cells.

Ghrelin is a 28-amino-acid peptide secreted predominantly by X/A-like cells of the gastric fundus. Ghrelin increases pancreatic beta-cell proliferation and survival via sequential activation of phosphatidylinositol-3 kinase (PI3K) and Akt. The transcription regulator Foxo1 is a prominent effector of PI3K/Akt; when it is inhibited, pancreatic beta-cells are protected against fatty-acid-induced apoptosis. We investigated the role of Foxo1 in the protective effect of ghrelin under lipotoxic conditions in the MIN6 pancreatic beta-cell line. Results showed that ghrelin promoted cell proliferation and attenuated palmitate-induced apoptosis in cultured MIN6 cells. Nuclear exclusion of Foxo1 was necessary for the function of ghrelin. Treatment of MIN6 cells with palmitate and ghrelin-induced rapid nuclear exclusion and phosphorylation of Foxo1. Unlike the JNK inhibitor SP600125, Akt inhibitor IV blocked the anti-lipotoxic effect of ghrelin and stimulated Foxo1 nuclear translocation. In addition, treatment with ghrelin combined with SP600125 showed a synergistic antiapoptotic effect in palmitate-treated MIN6 cells. Ghrelin also inhibited the endoplasmic reticulum stress pathway of apoptosis in MIN6 cells, decreased expression of cytoplasmic triglyceride, and downregulated gene expression of Bcl-2-associated X (BAX), sterol-response element-binding protein 1c (SREBP1c), and C/EBP homologous protein (CHOP-10). These findings suggest that ghrelin protects pancreatic beta-cells from lipotoxicity by inhibiting the nuclear translocation of Foxo1.