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.
Wang
Wei
W
Department of Endocrinology, First Hospital of China Medical University, No. 155, Nanjingbei Street, Heping District, Shenyang 110001, Liaoning, China.
Liu
Ying
Y
Chen
Ying
Y
Cao
Cuiping
C
Xiang
Ying
Y
Zhang
Dan
D
Han
Lingling
L
Zhao
Hong
H
Liu
Guoliang
G
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D054439:Ghrelin / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D019308:Palmitic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D051742:Transcription Factor CHOP / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics
D000873:Anthracenes; C494827:Bax protein, mouse; C497250:Ddit3 protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D054439:Ghrelin; D047428:Protein Kinase Inhibitors; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D051028:bcl-2-Associated X Protein; D051742:Transcription Factor CHOP; C432165:pyrazolanthrone; D012710:Serum Albumin, Bovine; D019308:Palmitic Acid; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3