Genistein attenuates D-GalN induced liver fibrosis/chronic liver damage in rats by blocking the TGF-β/Smad signaling pathways

Chem Biol Interact. 2017 Jan 5:261:80-85. doi: 10.1016/j.cbi.2016.11.022. Epub 2016 Nov 19.

Abstract

Background and aim: Genistein is a major isoflavonoid abundantly found in soy. Earlier genistein has been reported to possess protective effect against a multitude of disorders including cancer. Previously we demonstrated the protective effects of Genistein in d-Galactosamine (D-GalN) induced fulminant hepatic failure (FHF) in rats. In present study, we evaluated the hepatoprotective activity of Genistein in rat model of chronic liver damage and liver fibrosis.

Methods: Liver fibrosis was induced by intraperitoneal injection of D-GalN (250 mg/kg BW) twice a week for 12 weeks. Genistein (5 mg/kg BW) was given via intra-gastric route as co-treatment daily for 12 weeks.

Results: Genistein co-treatment significantly attenuated D-GalN-induced chronic liver damage and liver fibrosis as evident from a significant amelioration in functional impairment, including inhibition of the activation of Hepatic stellate cells (HSC), decreased expression in alpha smooth muscle actin (α-SMA) and accumulation of collagen matrix, and an elevation in serum alanine transaminase (ALT) and aspartate transaminase (AST) level. In addition Genistein co-treatment was associated with elevated expression of hepatic Smad7, which ultimately blunts the expression of TGF-β and the activation of TGF-β/Smad signaling. Furthermore Genistein significantly prevented the histopathological changes induced by D-GalN.

Conclusion: Our results suggest that Genistein could be a novel therapeutic/nutraceutical agent in treating chronic liver damage and liver fibrosis. In addition our study also suggests a possible mechanism of action in which Smad7-induced inhibition of TGF-β/Smad2/3 can be a central mechanism by which Genistein protects liver from chronic injury.

Keywords: Apoptosis; Cirrhosis; Oxidative stress; Steatohepatitis.

MeSH terms

  • Animals
  • Blotting, Western
  • Chronic Disease
  • Collagen / biosynthesis
  • Galactosamine
  • Genistein / pharmacology
  • Genistein / therapeutic use*
  • Hepatic Stellate Cells / drug effects
  • Hepatic Stellate Cells / metabolism
  • Hepatic Stellate Cells / pathology
  • In Situ Nick-End Labeling
  • Liver / drug effects
  • Liver / pathology*
  • Liver Cirrhosis / chemically induced*
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / pathology
  • Male
  • Rats, Wistar
  • Signal Transduction* / drug effects
  • Smad Proteins / metabolism*
  • Transforming Growth Factor beta / metabolism*
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism

Substances

  • Smad Proteins
  • Transforming Growth Factor beta
  • 3-nitrotyrosine
  • Tyrosine
  • Galactosamine
  • Collagen
  • Genistein