X-Box Binding Protein 1 Is Essential for Insulin Regulation of Pancreatic α-Cell Function

Akiyama, Mitoshi; Liew, Chong Wee; Lu, Shusheng; Hu, Jiang; Martínez, Rachael N.; Hambro, Ben; Kennedy, Robert T.; Kulkarni, Rohit

doi:10.2337/db12-1747

Cited by 55 publications

(62 citation statements)

References 50 publications

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“…In support of this conclusion, XBP1-deficient cells have reduced AKT phosphorylation without changes in PTEN expression compared with JunB KD cells. XBP1 has been shown to modulate AKT activity in other cell types, 31,42 and XBP1 may directly bind PI3K, facilitating AKT phosphorylation in endothelial cells. 43 JunB may also modulate AKT phosphorylation through a XBP1-dependent improvement of the ER folding capacity and consequent restoration of mTOR or via inhibition of protein phosphatase 2A, two important pathways previously shown to regulate AKT.…”

Section: Discussionmentioning

confidence: 99%

JunB protects β-cells from lipotoxicity via the XBP1–AKT pathway

et al. 2014

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Diets rich in saturated fats may contribute to the loss of pancreatic b-cells in type 2 diabetes. JunB, a member of the activating protein 1 (AP-1) transcription factor family, promotes b-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 b-cell protection from lipotoxicity. The saturated fatty acid palmitate decreased JunB expression, and this loss may contribute to b-cell apoptosis, as overexpression of JunB protected cells from lipotoxicity. Array analysis of JunB-deficient b-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/EBPd 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 b-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 b-cell protection against palmitate-induced apoptosis. JunB and XBP1 knockdown or IRE1 inhibition decreased AKT activation by cAMP, leading to b-cell apoptosis. In conclusion, JunB modulates the b-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 b-cell death. These findings elucidate novel b-cell-protective signal transduction in type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

JunB protects β-cells from lipotoxicity via the XBP1–AKT pathway

et al. 2014

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“…Mice with alpha cell-specific disruption of XBP1 expression (alpha-XBP1KO) [140] exhibit altered glucagon secretion as a result of increased ER stress that is not directly associated with alpha cell mass or growth. Surprisingly, prolonged XBP1 overproduction in rat islet cells impaired glucose-stimulated insulin secretion, BAX (BCL2-associated X protein) translocation, cytochrome c release and activation of caspase 3 and beta cell apoptosis [141].…”

Section: Old Agementioning

confidence: 99%

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

Mezza

Kulkarni

2014

Diabetologia

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Regeneration of mature cells that produce functional insulin represents a major focus and a challenge of current diabetes research aimed at restoring beta cell mass in patients with most forms of diabetes, as well as in ageing. The capacity to adapt to diverse physiological states during life and the consequent ability to cope with increased metabolic demands in the normal regulation of glucose homeostasis is a distinctive feature of the endocrine pancreas in mammals. Both beta and alpha cells, and presumably other islet cells, are dynamically regulated via nutrient, neural and/or hormonal activation of growth factor signalling and the post-transcriptional modification of a variety of genes or via the microbiome to continually maintain a balance between regeneration (e.g. proliferation, neogenesis) and apoptosis. Here we review key regulators that determine islet cell mass at different ages in mammals. Understanding the chronobiology and the dynamics and agedependent processes that regulate the relationship between the different cell types in the overall maintenance of an optimally functional islet cell mass could provide important insights into planning therapeutic approaches to counter and/or prevent the development of diabetes.

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“…It is worth noting that our data showed that IRE1α may modulate Akt phosphorylation through an XBP1 dependent manner as well. In fact, the regulatory role of XBP1s on Akt activity has also been reported in other cell types (33,34). Besides, an earlier study reported that in islets of db/db mice, increased activation of xbp1 mRNA was observed, presumably a compensatory mechanism to inhibit ER stress and β cell apoptosis induced by obesity (35).…”

Section: Discussionmentioning

confidence: 89%

Exendin‑4 protects INS‑1 cells against palmitate‑induced apoptosis through the IRE1α‑Xbp1 signaling pathway

Jiang

Wan

2018

Exp Ther Med

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Abstract. The anti-apoptotic effect of the incretin analog, exendin-4 (EX-4) on pancreatic β cells is mediated via the activation of protein kinase B (Akt) signaling, and its effect is partly produced through the inhibition of endoplasmic reticulum (ER) stress. However, the molecular mechanisms that underlie the effect of EX-4 on the suppression of ER stress and the upregulation of Akt signaling are poorly understood. Inositol-requiring enzyme 1 (IRE1), a member of the ER-localized transmembrane protein family, activates its downstream transcription factor X-box binding protein 1 (XBP1) to mediate a key part of the cellular unfolded protein response in order to cope with ER stress. Using the clonal rat pancreatic β cell line INS-1, the present study produced an in vitro model of ER stress using palmitate (PA) in order to determine whether the beneficial effect of EX-4 under ER stress was regulated by the IRE1α-Xbp1 signaling pathway. The results demonstrated that the reduction in ER stress and the activation Akt by EX-4 may be associated with the upregulation of IRE1α phosphorylation and the splicing of Xbp1 mRNA, which improved PA-reduced cell viability. This effect was partially abrogated by the knockdown of IRE1α with small interfering RNA. Additionally, cellular IRE1α was phosphorylated by the protein kinase A (PKA) associated with EX-4 and the activation of IRE1α, as IRE1α phosphorylation was attenuated by the inhibition of PKA with its inhibitor. In conclusion, the data identified the IRE1α-Xbp1 signaling pathway as an essential mediator that associates EX-4 with the intracellular mechanism that inhibits ER stress and activates Akt in order to regulate β cell survival. This may provide important evidence for the use of EX-4 in treatments for type 2 diabetes.

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X-Box Binding Protein 1 Is Essential for Insulin Regulation of Pancreatic α-Cell Function

Cited by 55 publications

References 50 publications

JunB protects β-cells from lipotoxicity via the XBP1–AKT pathway

JunB protects β-cells from lipotoxicity via the XBP1–AKT pathway

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

Exendin‑4 protects INS‑1 cells against palmitate‑induced apoptosis through the IRE1α‑Xbp1 signaling pathway

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