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Knockdown of IL4I1 Improved High Glucose-evoked Insulin Resistance in HepG2 Cells by Alleviating Inflammation and Lipotoxicity Through AHR Activation

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Abstract

Insulin resistance (IR) is one of the leading causes of Type 2 diabetes mellitus (T2DM). Inflammation, as a result of the disordered immune response, plays important roles in IR and T2DM. Interleukin-4-induced gene 1 (IL4I1) has been shown to regulate immune response and be involved in inflammation progress. However, there was little known about its roles in T2DM. Here, high glucose (HG)-treated HepG2 cells were used for T2DM investigation in vitro. Our results indicated that the expression of IL4I1 was up-regulated in peripheral blood samples of T2DM-patients and HG-induced HepG2 cells. The silencing of IL4I1 alleviated the HG-evoked IR through elevating the expressions of p-IRS1, p-AKT and GLUT4, and enhancing glucose consumption. Furthermore, IL4I1 knockdown inhibited inflammatory response by reducing the levels of inflammatory mediators, and suppressed the accumulation of lipid metabolites triglyceride (TG) and palmitate (PA) in HG-induced cells. Notably, IL4I1 expression was positively correlated with aryl hydrocarbon receptor (AHR) in peripheral blood samples of T2DM-patients. The silencing of IL4I1 inhibited the AHR signaling by reducing the HG-induced expressions of AHR and CYP1A1. Subsequent experiments confirmed that 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an agonist of AHR, reversed the suppressive effects of IL4I1 knockdown on HG-caused inflammation, lipid metabolism and IR in cells. In conclusion, we found that the silencing of IL4I1 attenuated inflammation, lipid metabolism and IR in HG-induced cells via inhibiting AHR signaling, suggesting that IL4I1 might be a potential therapy target for T2DM.

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Data Availability

The data and materials used to support the findings of this study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the Key Research and Development Program of Shaanxi (2023-YBSF-404).

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Authors and Affiliations

  1. Department of Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, 710061, Xi’an, Shaanxi, China, NO. 76, Yanta West Road, Yanta District

    Lin Run & Hongzhi Sun

  2. Department of Endocrinology, Xi’an Central Hospital Affiliated to Medical College of Xi’an Jiaotong University, 710003, Xi’an, Shaanxi, China

    Lin Run & Zhufang Tian

  3. Department of Endocrinology, The Affiliated Guangren Hospital, Xi’an Jiaotong University College of Medicine, 710004, Xi’an, Shaanxi, China

    Lin Xu

  4. Department of Medicine Interdisciplinary Research, Xi’an Ninth Hospital Affiliated to Medical College of Xi’an Jiaotong University, 710054, Xi’an, Shaanxi, China

    Junhui Du

  5. Clinical Laboratory, Xi’an Central Hospital Affiliated to Medical College of Xi’an Jiaotong University, 710003, Xi’an, Shaanxi, China

    Nan Li

  6. Department of Nuclear Medicine, Xi’an Central Hospital Affiliated to Medical College of Xi’an Jiaotong University, 710003, Xi’an, Shaanxi, China

    Qi Wang

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  1. Lin Run
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Zhufang Tian, Lin Xu, Junhui Du, Nan Li, Qi Wang and Hongzhi Sun. The first draft of the manuscript was written by Lin Run and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Hongzhi Sun.

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This study was approved by the ethic committee of Xi’an Jiaotong University Health Science Center and performed according to the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Run, L., Tian, Z., Xu, L. et al. Knockdown of IL4I1 Improved High Glucose-evoked Insulin Resistance in HepG2 Cells by Alleviating Inflammation and Lipotoxicity Through AHR Activation. Appl Biochem Biotechnol 195, 6694–6707 (2023). https://doi.org/10.1007/s12010-023-04399-9

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