JunB protects β-cells from lipotoxicity via the XBP1-AKT pathway.
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.
Laboratory of Experimental Medicine and ULB Center of Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
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Cunha
Laboratory of Experimental Medicine and ULB Center of Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
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Gurzov
Laboratory of Experimental Medicine and ULB Center of Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
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Naamane
Laboratory of Experimental Medicine and ULB Center of Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
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Ortis
Laboratory of Experimental Medicine and ULB Center of Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
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Cardozo
Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.
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Bugliani
Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.
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Marchetti
Laboratory of Experimental Medicine and ULB Center of Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
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Eizirik
1] Laboratory of Experimental Medicine and ULB Center of Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium [2] Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium.
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D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; C581727:JunB protein, human; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605545:Xbp1 protein, rat; D051057:Proto-Oncogene Proteins c-akt