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Fibroblast growth factor (FGF21) protects mouse liver against d-galactose-induced oxidative stress and apoptosis via activating Nrf2 and PI3K/Akt pathways

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Abstract

FGF21 is recently discovered with pleiotropic effects on glucose and lipid metabolism. However, the potential protective effect of FGF21 against d-gal-induced injury in the liver has not been demonstrated. The aim of this study is to investigate the pathophysiological role of FGF21 on hepatic oxidative injury and apoptosis in mice induced by d-gal. The 3-month-old Kunming mice were subcutaneously injected with d-gal (180 mg kg−1 d−1) for 8 weeks and administered simultaneously with FGF21 (5 or 1 mg kg−1 d−1). Our results showed that the administration of FGF21 significantly alleviated histological lesion including structure damage, degeneration, and necrosis of hepatocytes induced by d-gal, and attenuated the elevation of liver injury markers, serum AST, and ALP in a dose-dependent manner. FGF21 treatment also suppressed d-gal-induced profound elevation of ROS production and oxidative stress, as evidenced by an increase of the MDA level and depletion of the intracellular GSH level in the liver, and restored the activities of antioxidant enzymes SOD, CAT, GSH-Px, and T-AOC. Moreover, FGF21 treatment increased the nuclear abundance of Nrf2 and subsequent up regulation of several antioxidant genes. Furthermore, a TUNEL assay showed that d-gal-induced apoptosis in the mouse liver was significantly inhibited by FGF21. The expression of caspase-3 was markedly inhibited by the treatment of FGF21 in the liver of d-gal-treated mice. The levels of PI3K and PBK/Akt were also largely enhanced, which in turn inactivated pro-apoptotic signaling events, restoring the balance between pro- and anti-apoptotic Bcl-2 and Bax proteins in the liver of d-gal-treated mice. In conclusion, these results suggest that FGF21 protects the mouse liver against d-gal-induced hepatocyte oxidative stress via enhancing Nrf2-mediated antioxidant capacity and apoptosis via activating PI3K/Akt pathway.

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Abbreviations

FGF21:

Fibroblast growth factor 21

d-Gal:

d-Galactose

AST:

Aspartate aminotransferase

ALP:

Alkaline phosphatase

ROS:

Reactive oxygen species

MDA:

Malondialdehyde

GSH:

Glutathione

SOD:

Superoxide dismutase

CAT:

Catalase

GSH-Px:

Glutathione peroxidase

T-AOC:

Total antioxidation capability

Nrf2:

Nuclear factor erythroid 2-related factor 2

TUNEL:

Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling

PI3K:

Phosphoinositide-3-kinase

PBK/Akt:

Protein kinase B

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Acknowledgments

Yinhang Yu, Fuliang Bai, Wenfei Wang, and Deshan Li conceived and designed the experiments. Yinhang Yu, Yaonan Liu, Yongbi Yang, Qingyan Yuan, Dehua Zou, Tong Zhang, Siming Li, Susu Qu, Guiyou Tian, and YunYe Liu performed the experiments. Yin hang Yu, Guiping Ren, and Deshan Li analyzed the data. Yinhang Yu wrote the paper. Deshan Li revised the paper.

Conflict of interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Bio-pharmaceutical Lab, Life Science College, Northeast Agricultural University, Harbin, 150030, China

    Yinhang Yu, Fuliang Bai, Yaonan Liu, Yongbi Yang, Qingyan Yuan, Guiyou Tian, Liying Song, Tong Zhang, YunYe Liu, Wenfei Wang, Guiping Ren & Deshan Li

  2. Key Laboratory of Agricultural Biological Function Gene, Northeast Agricultural University, Harbin, 150030, China

    Wenfei Wang, Guiping Ren & Deshan Li

  3. Harbin University of Commerce, Harbin, 150028, China

    Siming Li

  4. Institute of Psychology, Chinese Academy of Sciences, Beijing, 100101, China

    Susu Qu

  5. Heilongjiang Bayi Agricultural University, Daqing, 163319, China

    Dehua Zou

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  1. Yinhang Yu
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Correspondence to Guiping Ren or Deshan Li.

Additional information

Yinhang Yu and Fuliang Bai have contributed equally to this study and are co-first authors.

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Yu, Y., Bai, F., Liu, Y. et al. Fibroblast growth factor (FGF21) protects mouse liver against d-galactose-induced oxidative stress and apoptosis via activating Nrf2 and PI3K/Akt pathways. Mol Cell Biochem 403, 287–299 (2015). https://doi.org/10.1007/s11010-015-2358-6

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