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

Mol Med Rep. 2019 Sep;20(3):2450-2458. doi: 10.3892/mmr.2019.10457. Epub 2019 Jul 2.


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.

MeSH terms

  • Adiponectin / metabolism*
  • Antioxidants / pharmacology*
  • Ascorbic Acid / pharmacology*
  • Fibroblast Growth Factors / metabolism*
  • Hep G2 Cells
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Non-alcoholic Fatty Liver Disease / drug therapy
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism*
  • Signal Transduction / drug effects


  • ADIPOQ protein, human
  • Adiponectin
  • Antioxidants
  • fibroblast growth factor 21
  • Fibroblast Growth Factors
  • FGFR2 protein, human
  • Receptor, Fibroblast Growth Factor, Type 2
  • Ascorbic Acid