Reduced Expression of Chl1 gene Impairs Insulin Secretion by Down-Regulating the Expression of Key Molecules of β-cell Function

Abstract

Silencing of <i>Chl1</i> gene expression has been previously reported to reduce insulin secretion. Nevertheless, the mechanism underlying this effect remains unclear. In this study, we performed a serial of studies to investigate how <i>Chl1</i> affects insulin secretion in INS-1 cells. RNA-sequencing was used to investigate the expression of <i>CHL1</i> in human adipose, liver, muscle, and human islets. Silencing of <i>Chl1</i> in INS-1 cells was done to assess its impact on the insulin secretion, content, cell viability, and apoptosis. In addition, gene set enrichment analysis (GSEA) was performed to identify possible molecular signatures that associate with <i>Chl1</i> expression silencing.RNA sequencing data revealed a high expression of <i>CHL1</i> in pancreatic islets and adipose tissues compared to liver and muscles tissues. Diabetic islets exhibited a lower expression of <i>CHL1</i> as compared to non-diabetic islets. <i>CHL1</i> expression was found to correlate positively with insulin secretory index, <i>GLP1R</i> but inversely with HbA_1c and BMI. Silencing of <i>Chl1</i> in INS-1 cells markedly reduced insulin content and secretion. The expression of key molecules of β-cell function including <i>Insulin, Pdx1</i>, <i>Gck, Glut2,</i> and <i>Insrβ</i> was down-regulated in <i>Chl1</i>-silenced cells at transcriptional and translational levels. Cell viability, apoptosis, and proliferation rate were not affected. GSEA showed that the insulin-signaling pathway was influenced in <i>Chl1</i>-silenced cells. Silencing of Chl1 impairs β-cell function by disrupting the activity of key signaling pathways of importance for insulin biosynthesis and secretion.