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JunB protects β-cells from lipotoxicity via the XBP1-AKT pathway.
- Source :
-
Cell death and differentiation [Cell Death Differ] 2014 Aug; Vol. 21 (8), pp. 1313-24. Date of Electronic Publication: 2014 May 02. - Publication Year :
- 2014
-
Abstract
- Diets rich in saturated fats may contribute to the loss of pancreatic β-cells in type 2 diabetes. JunB, a member of the activating protein 1 (AP-1) transcription factor family, promotes β-cell survival and mediates part of the beneficial effects of GLP-1 agonists. In this study we interrogated the molecular mechanisms involved in JunB-mediated β-cell protection from lipotoxicity. The saturated fatty acid palmitate decreased JunB expression, and this loss may contribute to β-cell apoptosis, as overexpression of JunB protected cells from lipotoxicity. Array analysis of JunB-deficient β-cells identified a gene expression signature of a downregulated endoplasmic reticulum (ER) stress response and inhibited AKT signaling. JunB stimulates XBP1 expression via the transcription factor c/EBPδ during ER stress, and forced expression of XBP1s rescued the viability of JunB-deficient cells, constituting an important antiapoptotic mechanism. JunB silencing inhibited AKT activation and activated the proapoptotic Bcl-2 protein BAD via its dephosphorylation. BAD knockdown reversed lipotoxic β-cell death potentiated by JunB siRNA. Interestingly, XBP1s links JunB and AKT signaling as XBP1 knockdown also reduced AKT phosphorylation. GLP-1 agonists induced cAMP-dependent AKT phosphorylation leading to β-cell protection against palmitate-induced apoptosis. JunB and XBP1 knockdown or IRE1 inhibition decreased AKT activation by cAMP, leading to β-cell apoptosis. In conclusion, JunB modulates the β-cell ER stress response and AKT signaling via the induction of XBP1s. The activation of the JunB gene network and the crosstalk between the ER stress and AKT pathway constitute a crucial defense mechanism by which GLP-1 agonists protect against lipotoxic β-cell death. These findings elucidate novel β-cell-protective signal transduction in type 2 diabetes.
- Subjects :
- Animals
DNA-Binding Proteins genetics
Diabetes Mellitus, Type 2 enzymology
Diabetes Mellitus, Type 2 genetics
Diabetes Mellitus, Type 2 metabolism
Female
Humans
Insulin-Secreting Cells enzymology
Male
Middle Aged
Phosphorylation
Proto-Oncogene Proteins c-akt metabolism
Rats
Regulatory Factor X Transcription Factors
Signal Transduction
Transcription Factors genetics
X-Box Binding Protein 1
DNA-Binding Proteins metabolism
Insulin-Secreting Cells metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5403
- Volume :
- 21
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Cell death and differentiation
- Publication Type :
- Academic Journal
- Accession number :
- 24786832
- Full Text :
- https://doi.org/10.1038/cdd.2014.53