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Molecular and Cellular Biochemistry

, Volume 403, Issue 1–2, pp 287–299 | Cite as

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

  • Yinhang Yu
  • Fuliang Bai
  • Yaonan Liu
  • Yongbi Yang
  • Qingyan Yuan
  • Dehua Zou
  • Susu Qu
  • Guiyou Tian
  • Liying Song
  • Tong Zhang
  • Siming Li
  • YunYe Liu
  • Wenfei Wang
  • Guiping Ren
  • Deshan Li
Article

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.

Keywords

FGF21 d-Gal Nrf2-mediated antioxidant capacity PI3K/AKT Apoptosis 

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

Notes

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.

Supplementary material

11010_2015_2358_MOESM1_ESM.docx (456 kb)
Supplementary material 1 (DOCX 456 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Yinhang Yu
    • 1
  • Fuliang Bai
    • 1
  • Yaonan Liu
    • 1
  • Yongbi Yang
    • 1
  • Qingyan Yuan
    • 1
  • Dehua Zou
    • 5
  • Susu Qu
    • 4
  • Guiyou Tian
    • 1
  • Liying Song
    • 1
  • Tong Zhang
    • 1
  • Siming Li
    • 3
  • YunYe Liu
    • 1
  • Wenfei Wang
    • 1
    • 2
  • Guiping Ren
    • 1
    • 2
  • Deshan Li
    • 1
    • 2
  1. 1.Bio-pharmaceutical Lab, Life Science CollegeNortheast Agricultural UniversityHarbinChina
  2. 2.Key Laboratory of Agricultural Biological Function GeneNortheast Agricultural UniversityHarbinChina
  3. 3.Harbin University of CommerceHarbinChina
  4. 4.Institute of PsychologyChinese Academy of SciencesBeijingChina
  5. 5.Heilongjiang Bayi Agricultural UniversityDaqingChina

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