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Egr-1 transactivates WNT5A gene expression to inhibit glucose-induced β-cell proliferation
Abstract:
Selective β-cell loss is a characteristic of type 2 diabetes mellitus (T2DM). Inhibition of glucose-stimulated β-cell proliferation is one of the in vivo results of the lipotoxicity of saturated fatty acids (SFAs). However, the mechanism by which lipotoxicity inhibits β-cell proliferation is still unclear. In this study, we found palmitate, a saturated fatty acid, inhibited the β-cell proliferation induced by high glucose through the induction of Wnt5a expression in vitro and in vivo. We also found that Wnt5a was both sufficient and necessary for inhibition of β-cell proliferation. Additionally, Egr-1, but not NF-κB, FOXO1, Smad2, Smad3, SP1 or SP3 mediated the expression of Wnt5a. Deletion and site-directed mutagenesis of the WNT5A promoter revealed that activation of WNT5A gene transcription depends primarily on a putative Egr-binding sequence between nucleotides -52 to -44, upstream of the transcription start site. Furthermore, Egr-1 bound directly to this sequence in response to palmitate treatment, both in vitro and in vivo. Moreover, after mice islets were treated with Egr inhibitors, the expression of Wnt5a decreased significantly and the glucose-induced β-cell proliferation inhibited by palmitate was resumed. These findings establish Wnt5a as an Egr-1 target gene in β-cells, uncovering a novel Egr-1/Wnt5a pathway by which saturated free fatty acids block glucose-induced β-cell proliferation. Our study lends support for the potential of Egr-1 inhibitors or Wnt5a antibodies as therapeutics for the treatment of T2DM.
Insights
Saturated fatty acids block glucose-induced beta-cell proliferation in type 2 diabetes by inducing Wnt5a expression via Egr-1. Inhibiting Egr-1 or Wnt5a may offer new type 2 diabetes treatments.
Area of Science:
- Endocrinology
- Molecular Biology
- Metabolic Diseases
Background:
- Selective beta-cell loss characterizes type 2 diabetes mellitus (T2DM).
- Saturated fatty acids (SFAs) cause lipotoxicity, inhibiting glucose-stimulated beta-cell proliferation, but the mechanism remains unclear.
- Understanding this mechanism is crucial for T2DM therapeutic development.
Purpose of the Study:
- To elucidate the molecular mechanism by which SFAs inhibit beta-cell proliferation.
- To identify key signaling pathways and molecules involved in SFA-induced beta-cell dysfunction.
- To explore potential therapeutic targets for T2DM.
Main Methods:
- In vitro and in vivo experiments using palmitate (an SFA) and beta-cells/mouse islets.
- Analysis of Wnt5a expression and its role in beta-cell proliferation.
- Investigation of transcription factors, including Egr-1, mediating Wnt5a expression.
- Promoter analysis and chromatin immunoprecipitation assays to identify Egr-1 binding sites.
- Treatment with Egr inhibitors to assess functional recovery.
Main Results:
- Palmitate inhibited glucose-induced beta-cell proliferation by inducing Wnt5a expression.
- Wnt5a was both sufficient and necessary for this inhibitory effect.
- Egr-1, not other tested factors, mediated Wnt5a expression by binding to a specific promoter sequence.
- Egr-1 inhibition restored beta-cell proliferation in palmitate-treated islets.
Conclusions:
- A novel Egr-1/Wnt5a pathway mediates SFA-induced inhibition of beta-cell proliferation.
- Egr-1 acts as a critical transcription factor regulating Wnt5a in response to lipotoxicity.
- Egr-1 inhibitors or Wnt5a antibodies represent potential therapeutic strategies for T2DM.
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