Autophagy Regulates Pancreatic Beta Cell Death in Response to Pdx1 Deficiency and Nutrient Deprivation

被引:100
作者
Fujimoto, Kei [1 ]
Hanson, Piia T. [1 ]
Tran, Hung [1 ]
Ford, Eric L. [1 ]
Han, Zhiqiang [1 ]
Johnson, James D. [1 ]
Schmidt, Robert E. [2 ]
Green, Karen G. [2 ]
Wice, Burton M. [1 ]
Polonsky, Kenneth S. [1 ]
机构
[1] Washington Univ, Sch Med, Div Endocrinol Metab & Lipid Res, Dept Internal Med,Barnes Jewish Hosp, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Div Neuropathol, Dept Pathol & Immunol,Barnes Jewish Hosp, St Louis, MO 63110 USA
关键词
HIGH-FAT DIET; MICE; APOPTOSIS; TUMORIGENESIS; BECLIN-1; DISEASE; FUSION; ISLETS; GENE; MASS;
D O I
10.1074/jbc.M109.041616
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
There are three types of cell death; apoptosis, necrosis, and autophagy. The possibility that activation of the macroautophagy (autophagy) pathway may increase beta cell death is addressed in this study. Increased autophagy was present in pancreatic islets from Pdx1(+/-) mice with reduced insulin secretion and beta cell mass. Pdx1 expression was reduced in mouse insulinoma 6 (MIN6) cells by delivering small hairpinRNAsusing a lentiviral vector. The MIN6 cells died after 7 days of Pdx1 deficiency, and autophagy was evident prior to the onset of cell death. Inhibition of autophagy prolonged cell survival and delayed cell death. Nutrient deprivation increased autophagy in MIN6 cells and mouse and human islets after starvation. Autophagy inhibition partly prevented amino acid starvation-induced MIN6 cell death. The in vivo effects of reduced autophagy were studied by crossing Pdx1(+/-) mice to Becn1(+/-) mice. After 1 week on a high fat diet, 4-week-old Pdx1(+/-) Becn1(+/-) mice showed normal glucose tolerance, preserved beta cell function, and increased beta cell mass compared with Pdx1(+/-) mice. This protective effect of reduced autophagy had worn off after 7 weeks on a high fat diet. Increased autophagy contributes to pancreatic beta cell death in Pdx1 deficiency and following nutrient deprivation. The role of autophagy should be considered in studies of pancreatic beta cell death and diabetes and as a target for novel therapeutic intervention.
引用
收藏
页码:27664 / 27673
页数:10
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