Fibroblast growth factor 21 attenuates hepatic fibrogenesis through TGF-β/smad2/3 and NF-κB signaling pathways

Toxicol Appl Pharmacol. 2016 Jan 1;290:43-53. doi: 10.1016/j.taap.2015.11.012. Epub 2015 Nov 22.

Abstract

Fibroblast growth factor 21 (FGF-21) is a secreted protein, which has anti-diabetic and lipocaic effects, but its ability to protect against hepatic fibrosis has not been studied. In this study, we investigated the ability of FGF-21 to attenuate dimethylnitrosamine (DMN)-induced hepatic fibrogenesis in mice and the mechanism of its action. Hepatic fibrosis was induced by injection of DMN, FGF-21 was administered to the mice once daily in association with DMN injection till the end of the experiment. Histopathological examination, tissue 4-hydroxyproline content and expressions of smooth muscle α-actin (α-SMA) and collagen I were measured to assess hepatic fibrosis. Ethanol/PDGF-BB-activated hepatic stellate cells (HSCs) were used to understand the mechanisms of FGF-21 inhibited hepatic fibrogenesis. Results showed that FGF-21 treatment attenuated hepatic fibrogenesis and was associated with a significant decrease in intrahepatic fibrogenesis, 4-hydroxyproline accumulation, α-SMA expression and collagen I deposition. FGF-21 treatment inhibited the activation of HSCs via down-regulating the expression of TGF-β, NF-κB nuclear translocation, phosphorylation levels of smad2/3 and IκBα. Besides, FGF-21 treatment caused activated HSC apoptosis with increasing expression of Caspase-3, and decreased the ratio of Bcl-2 to Bax. In conclusion, FGF-21 attenuates hepatic fibrogenesis and inhibits the activation of HSC warranting the use of FGF-21 as a potential therapeutic agent in the treatment of hepatic fibrosis.

Keywords: Fibroblast growth factor 21; Hepatic fibrogenesis; Hepatic stellate cells; NF-κB; TGF-β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Animals
  • Apoptosis / drug effects
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Dimethylnitrosamine / toxicity
  • Down-Regulation
  • Fibroblast Growth Factors / pharmacology*
  • Hepatic Stellate Cells / drug effects
  • Hepatic Stellate Cells / metabolism
  • Hydroxyproline / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / pathology
  • Male
  • Mice
  • Mice, Inbred ICR
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Signal Transduction*
  • Smad2 Protein / genetics
  • Smad2 Protein / metabolism*
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism

Substances

  • Actins
  • Bax protein, mouse
  • Collagen Type I
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta
  • alpha-smooth muscle actin, mouse
  • bcl-2-Associated X Protein
  • fibroblast growth factor 21
  • Bcl2 protein, mouse
  • Fibroblast Growth Factors
  • Casp3 protein, mouse
  • Caspase 3
  • Dimethylnitrosamine
  • Hydroxyproline