Egr-1 transactivates WNT5A gene expression to inhibit glucose-induced β-cell proliferation

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.

Source: Biochimica et Biophysica Acta (BBA) Gene Regulatory Mechanisms - July 18, 2018 Category: Genetics & Stem Cells Source Type: research