Autophagy inhibition attenuates the induction of anti-inflammatory effect of catalpol in liver fibrosis

Biomed Pharmacother. 2018 Jul;103:1262-1271. doi: 10.1016/j.biopha.2018.04.156. Epub 2018 May 7.

Abstract

Autophagy has been regarded as an inflammation-associated defensive mechanism against chronic liver disease, which has been highlighted as a novel therapeutic target for the treatment of liver fibrosis. We herein aimed to study the effects of catalpol on liver fibrosis in vivo and in vitro, and to elucidate the role of autophagy in catalpol-induced anti-inflammation. Catalpol protected the liver against CCl4-induced injury, as evidenced by mitigated hepatic steatosis, necrosis, and fibrotic septa. Catalpol decreased the serum levels of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase and bilirubin as well as the liver/body weight ratio. Masson and sirius red staining along with hydroxyproline detection showed that catalpol decreased collagen deposition significantly compared to that of the model group. Catalpol inhibited CCl4-induced liver fibrosis, manifested as decreased expressions of α-SMA, fibronectin and α1(I)-procollagen at both transcriptional and translational levels. Inflammatory factors, such as IL-1β, TNF-α, IL-18, IL-6 and COX-2, were significantly elevated in rats receiving CCl4 and down-regulated by catalpol in a dose-dependent manner in vivo. Western blot and immunofluorescence assay revealed that catalpol activated the autophagy of rats with CCl4-caused liver fibrosis, as indicated by up-regulation of LC3-II and beclin1 and down-regulation of P62. The results of in vitro experiments were consistent. Interestingly, inhibition or depletion of autophagy by LY294002 or Atg5 siRNA significantly attenuated catalpol-induced anti-inflammatory effects on activated hepatic stellate cells in vitro. In conclusion, catalpol relieved liver fibrosis mainly by inhibiting inflammation, and autophagy inhibition attenuated the catalpol-induced anti-inflammatory effect on liver fibrosis.

Keywords: Autophagy; Catalpol; Inflammation; Liver fibrosis; Molecular mechanism.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use*
  • Autophagy / drug effects*
  • Carbon Tetrachloride
  • Disease Models, Animal
  • Hepatic Stellate Cells / drug effects
  • Hepatic Stellate Cells / metabolism
  • Hepatic Stellate Cells / pathology
  • Inflammation / drug therapy
  • Inflammation / pathology
  • Iridoid Glucosides / pharmacology
  • Iridoid Glucosides / therapeutic use*
  • Liver / drug effects
  • Liver / injuries
  • Liver / pathology
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / pathology*
  • Male
  • Protective Agents / pharmacology
  • Protective Agents / therapeutic use
  • Rats, Sprague-Dawley

Substances

  • Anti-Inflammatory Agents
  • Iridoid Glucosides
  • Protective Agents
  • catalpol
  • Carbon Tetrachloride