Naringenin attenuates the progression of liver fibrosis via inactivation of hepatic stellate cells and profibrogenic pathways

Eur J Pharmacol. 2019 Dec 15;865:172730. doi: 10.1016/j.ejphar.2019.172730. Epub 2019 Oct 13.

Abstract

There is no effective treatment for hepatic fibrosis. Previously, we demonstrated that naringenin possesses the ability to prevent experimental chronic liver damage. Therefore, the objective of this work was to investigate whether naringenin could reverse carbon tetrachloride (CCl4)-induced fibrosis in rats and, if so, to search for the mechanisms involved. CCl4 was given to male Wistar rats (400 mg/kg, three times per week, i. p.) for 12 weeks; naringenin (100 mg/kg twice per day, p. o.) was administered from weeks 9-12 of the CCl4 treatment. Liver damage and oxidative stress markers were measured. Masson's trichrome, hematoxylin-eosin staining and immunohistochemistry were performed. Zymography assays for MMP-9 and MMP-2 were carried out. TGF-β, CTGF, Col-I, MMP-13, NF-κB, IL-1β, IL-10, Smad7, pSmad3 and pJNK protein levels were determined by western blotting. In addition, α-SMA and Smad3 protein and mRNA levels were studied. Naringenin reversed liver damage, biochemical and oxidative stress marker elevation, and fibrosis and restored normal MMP-9 and MMP-2 activity. The flavonoid also preserved NF-κB, IL-1β, IL-10, TGF-β, CTGF, Col-I, MMP-13 and Smad7 protein levels. Moreover, naringenin decreased JNK activation and Smad3 phosphorylation in the linker region. Finally, α-SMA and Smad3 protein and mRNA levels were reduced by naringenin administration. The results of this study demonstrate that naringenin blocks oxidative stress, inflammation and the TGF-β-Smad3 and JNK-Smad3 pathways, thereby carrying out its antifibrotic effects and making it a good candidate to treat human fibrosis, as previously demonstrated in toxicological and clinical studies.

Keywords: ECM; Fibrosis; HSC; JNK; NF-κB; Smad3; TGF-β.

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cell Differentiation / drug effects
  • Collagen / metabolism
  • Disease Progression*
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism
  • Flavanones / pharmacology*
  • Flavanones / therapeutic use
  • Hepatic Stellate Cells / drug effects*
  • Hepatic Stellate Cells / pathology*
  • Liver Cirrhosis / drug therapy
  • Liver Cirrhosis / pathology*
  • Male
  • Proteolysis / drug effects
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects

Substances

  • Biomarkers
  • Flavanones
  • Collagen
  • naringenin