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

J. Lyu; H. Imachi; H. Iwama; H. Zhang; K. Murao

doi:10.1055/s-0035-1569272

Hormone and Metabolic Research, Inhaltsverzeichnis

Horm Metab Res 2016; 48(05): 338-344
DOI: 10.1055/s-0035-1569272

Endocrine Research

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

J. Lyu

¹Department of Cell Biology, Jiangsu Key Laboratory of Stem Cell Research, Medical College of Soochow University, Ren Ai Road, Suzhou Industrial Park, Suzhou, China

²Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan

,

H. Imachi

²Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan

,

H. Iwama

³Life Science Research Center, Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan

,

H. Zhang

¹Department of Cell Biology, Jiangsu Key Laboratory of Stem Cell Research, Medical College of Soochow University, Ren Ai Road, Suzhou Industrial Park, Suzhou, China

,

K. Murao

²Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa, Japan

› Institutsangaben

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.

Key words

ABCA1 - pancreatic beta cells - PI3K/Akt - FoxO1 - cholesterol efflux

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