Erythropoietin ameliorates PA-induced insulin resistance through the IRS/AKT/FOXO1 and GSK-3β signaling pathway, and inhibits the inflammatory response in HepG2 cells

Zhang,Hong; Ge,Zhijuan; Tang,Sunyinyan; Meng,Ran; Bi,Yan; Zhu,Dalong

doi:10.3892/mmr.2017.6810

Erythropoietin ameliorates PA-induced insulin resistance through the IRS/AKT/FOXO1 and GSK-3β signaling pathway, and inhibits the inflammatory response in HepG2 cells

Authors:
- Hong Zhang
- Zhijuan Ge
- Sunyinyan Tang
- Ran Meng
- Yan Bi
- Dalong Zhu
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Affiliations: Department of Endocrinology, Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
Published online on: June 20, 2017 https://doi.org/10.3892/mmr.2017.6810
Pages: 2295-2301

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Abstract

Erythropoietin (EPO) contributes to insulin resistance in fat and muscle. In the present study, the role and mechanism of EPO in hepatic insulin resistance were investigated in HepG2 cells. Hepatic insulin resistance was induced by palmitic acid (PA) in the HepG2 cells, which were then treated with EPO (5 or 10 U/ml) or specific phosphoinositide 3‑kinase (PI3K) inhibitors, wortmannin or LY294002. EPO treatment significantly increased glycogen levels and reduced the protein expression of phosphoenolpyruvate carboxykinase in the PA‑induced HepG2 cells. EPO also inhibited the serine phosphorylation of insulin receptor substrate (IRS)‑1 (Ser307) and IRS‑2 (Ser473), and increased the protein expression levels of PI3K, phosphorylated (p)‑protein kinase B (AKT), p‑forkhead box O1 (FOXO1) and p‑glycogen synthase kinase 3 (GSK‑3) β. In agreement with these result, the expression of p‑FOXO1 (Ser256) and p‑GSK‑3β (Ser9), downstream molecules of AKT, were enhanced by EPO treatment (P<0.05). The specific PI3K inhibitors, LY294002 and wortmannin, markedly inhibited the EPO‑mediated increases in p‑AKT (Ser473), p‑FOXO1 (Ser256) and p‑GSK‑3β (Ser9) in the PA‑induced HepG2 cells (P<0.05). The gene expression levels of tumor necrosis factor‑α, interleukin‑1β and monocyte chemoattractant protein‑1, and the p‑c‑Jun N‑terminal kinase (JNK)/total‑JNK ratio were markedly suppressed by EPO treatment. These findings suggested that EPO treatment improved hepatic glucose metabolism, potentially through the IRS/AKT/FOXO1 and GSK‑3β signaling pathway, which may be associated with its inhibitory effect on the inflammation-associated response.

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