Ascorbic acid attenuates cell stress by activating the fibroblast growth factor 21/fibroblast growth factor receptor 2/adiponectin pathway in HepG2 cells

Gu,Xinqian; Luo,Xiao; Wang,Yanxin; He,Zhangya; Li,Xiaomin; Wu,Kunjin; Zhang,Yifan; Yang,Yafeng; Ji,Jing; Luo,Xiaoqin

doi:10.3892/mmr.2019.10457

Ascorbic acid attenuates cell stress by activating the fibroblast growth factor 21/fibroblast growth factor receptor 2/adiponectin pathway in HepG2 cells

Authors:
- Xinqian Gu
- Xiao Luo
- Yanxin Wang
- Zhangya He
- Xiaomin Li
- Kunjin Wu
- Yifan Zhang
- Yafeng Yang
- Jing Ji
- Xiaoqin Luo
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Affiliations: Department of Nutrition and Food Safety, School of Public Health, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Clinical Nutrition, Xian Yang Central Hospital, Xianyang, Shaanxi 712000, P.R. China, Department of Obstetrics, Northwest Women and Children Hospital, Xi'an, Shaanxi 710061, P.R. China
Published online on: July 2, 2019 https://doi.org/10.3892/mmr.2019.10457
Pages: 2450-2458

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Abstract

Increasing prevalence of obesity‑induced non‑alcoholic fatty liver disease (NAFLD) and non‑alcoholic steatohepatitis (NASH) has been reported. Ascorbic acid (AA), also known as vitamin C, an excellent antioxidant, has been shown to exert beneficial effects on NAFLD; however, the underlying mechanisms are yet to be fully elucidated. In the present study, the role of AA on cell stress in tumor necrosis factor α (TNFα)‑treated HepG2 cells was investigated. Our findings revealed that exposure to AA effectively ameliorated TNFα‑induced cell stresses, including hypoxia, inflammation and endoplasmic reticulum (ER) stress by reducing the expression of Hif1α and its target genes (glucose transporter 1), pro‑inflammatory genes (monocyte chemoattractant 1) and ER stress‑related genes (glucose‑regulated protein, 78 kDa). AA also decreased the protein level of HIF1α. Additionally, AA significantly increased the secretion of total adiponectin and high molecular weight (HMW) adiponectin. Mechanistically, AA was determined to increase the expression of fibroblast growth factor 21 (FGF21) and its receptor, fibroblast growth factor receptor 2 (FGFR2). Knockdown of FGFR2 not only decreased the levels of total adiponectin and HMW adiponectin, but almost abolished the beneficial effects of AA in ameliorating cell stress. Collectively, the findings of our study demonstrated that AA may attenuate hepatocyte stress induced by TNFα via activation of the FGF21/FGFR2/adiponectin pathway. This could a novel mechanism of action of AA, and its potential for the treatment of NAFLD/NASH.

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