Insulin-like Growth Factor 1 Regulates the Expression of ATP-Binding Cassette Transporter A1 in Pancreatic Beta Cells

Abstract

ATP-binding cassette transporter A1 (ABCA1) in pancreatic beta cells influences insulin secretion and cholesterol homeostasis. The present study investigates whether insulin-like growth factor 1 (IGF-1), which mediates stimulation of ABCA1 gene expression, could also interfere with the phosphatidylinositol 3-kinase (PI3-K) cascade.ABCA1 expression was examined by real-time polymerase chain reaction (PCR), Western blot analysis, and a reporter gene assay in rat insulin-secreting INS-1 cells incubated with IGF-1. The binding of forkhead box O1 (FoxO1) protein to the ABCA1 promoter was assessed by a chromatin immunoprecipitation (ChIP) assay. ABCA1 protein levels increased in response to rising concentrations of IGF-1. Real-time PCR analysis showed a significant increase in ABCA1 mRNA expression. However, both effects were suppressed after silencing the IGF-1 receptor. In parallel with its effect on endogenous ABCA1 mRNA levels, IGF-1 induced the activity of a reporter construct containing the ABCA1 promoter, while it was abrogated by LY294002, a specific inhibitor of PI3-K. Constitutively active Akt stimulated activity of the ABCA1 promoter, and a dominant-negative mutant of Akt or mutagenesis of the FoxO1 response element in the ABCA1 promoter abolished the ability of IGF-1 to stimulate promoter activity. A ChIP assay showed that FoxO1 mediated its transcriptional activity by directly binding to the ABCA1 promoter region. The knockdown of FoxO1 disrupted the effect of IGF-1 on ABCA1 expression. Furthermore, IGF-1 promoted cholesterol efflux and reduced the pancreatic lipotoxicity. These results demonstrate that the PI3-K/Akt/FoxO1 pathway contributes to the regulation of ABCA1 expression in response to IGF-1 stimulation.

Pancreatic Beta-Cell Proliferation Induced by Estradiol-17β is Foxo1 Dependent

“…Foxo1 KD and inhibition reduced E2-dependent ERα transcriptional activity through the ERE, similar to the effect of Foxo1-ERα interaction on the ERE in MCF7 cells [26]. E2 enhanced Foxo1 phosphorylation in INS1-E and human islets, a known mechanism of Foxo1 nuclear export and inhibition of transcription [28,35]. E2 could thus act to limit its transcriptional collaboration with Foxo1 by time dependent induction of phosphorylation (proposed model ▶Fig.…”

“…In accord with the latter effects, Foxo1 haploinsufficiency enhances proliferation and restores β-cell mass in insulin receptor substrate-2-knockout and β-cell-specific Pdk1-knockout models of diabetes [23,24]. Foxo1 activity is regulated by post-translational modifications, primarily phosphorylation, which induces nuclear-cytoplasmic translocation thus inhibiting its transcriptional activity [25][26][27][28].…”

The impact of ATP-binding cassette transporters on metabolic diseases

“…However, there is a debate regarding whether the ABCA1 gene polymorphism is a genetic risk factor for T2DM [ 35 , 85 ]. Insulin-like growth factor 1 (IGF-1) can mediate the stimulation of ABCA1 gene expression by inducing the PI3-K/Akt/Forkhead box protein O1 (FoxO1) pathway [ 86 ]. In addition, the expression of ABCA1 and miR-27a can be increased and decreased, respectively, via GLP-1.…”

Effect of TNF-α on the expression of ABCA1 in pancreatic β-cells

“…The important role of β-cell ABCA1 in glucose homeostasis was further underscored by the finding that rosiglitazone increased β-cell ABCA1 expression (Brunham et al 2007). Furthermore, we previously found that exendin-4, a glucagon-like peptide-1 analog, and insulin-like growth factor-I, have stimulatory effects on ABCA-1 expression at the transcriptional level, thereby influencing insulin secretion in pancreatic β-cells (Li et al 2010, Lyu et al 2016.…”

“…To measure cellular cholesterol content concentration, we used a colorimetric assay that utilizes reagents widely used for the measurement of cholesterol in conjunction with a random-access chemistry analyzer ARCHITECT c8000 as described previously (Lyu et al 2016).…”