Hepatoprotective effects of ethyl pyruvate against CCl4-induced hepatic fibrosis via inhibition of TLR4/NF-κB signaling and up-regulation of MMPs/TIMPs ratio

Clin Res Hepatol Gastroenterol. 2018 Feb;42(1):72-81. doi: 10.1016/j.clinre.2017.04.008. Epub 2017 Jun 7.

Abstract

Background and aim: Liver fibrosis is a worldwide clinical issue. It has been well established that liver fibrosis is characterized of excessive extracellular matrix (ECM) deposition in chronically damaged livers. Accumulating evidences have suggested that ethyl pyruvate (EP) is a potential useful agent for preventing from hepatic injury. The aim of this study was to evaluate the protective effects of the EP against liver fibrosis induced by carbon tetrachloride (CCl4) in rats.

Method: Rats were randomly divided into control group, CCl4 group and CCl4+EP group, which with and without EP administration. Liver fibrosis was evaluated by serum biochemical parameters levels, Masson's trichromic staining and immunohistochemistry. Q-RTPCR was used to indicate genes expression. ELISA was used to detect proteins level.

Results: This study demonstrates that Toll-like receptors 4 (TLR4)/nuclear factor kappa B (NF-κB) signal is an important regulator of liver fibrosis while TLR4/NF-κB mRNA and protein levels reduced during HSCs activation. In addition, down-regulated high-mobility group box 1 (HMGB1) expression reduced NF-κB transcription and phosphorylation, which inhibited HSCs activation by blocking the TLR4 signal. Moreover, EP contributed to an increase in the ratio of matrix metalloproteinase (MMPs) to tissue inhibitor of matrix metalloproteinase (TIMPs), which might facilitate the degradation of the ECM. In CCl4-induced liver fibrosis rats, additional EP injection resulted in decreased ECM deposition and improved liver function.

Conclusion: In conclusion, the present findings indicated that EP might be an effective agent for anti-fibrotic therapy.

Keywords: Ethyl pyruvate; Hepatic fibrosis; Matrix metalloproteinase; Tissue inhibitor of matrix metalloproteinase.

MeSH terms

  • Animals
  • Carbon Tetrachloride / administration & dosage
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / prevention & control*
  • Male
  • Matrix Metalloproteinases / physiology*
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / physiology
  • Pyruvates / pharmacology*
  • Pyruvates / therapeutic use*
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*
  • Tissue Inhibitor of Metalloproteinases / physiology*
  • Toll-Like Receptor 4 / antagonists & inhibitors*
  • Toll-Like Receptor 4 / physiology
  • Up-Regulation / drug effects*

Substances

  • NF-kappa B
  • Pyruvates
  • Tissue Inhibitor of Metalloproteinases
  • Tlr4 protein, rat
  • Toll-Like Receptor 4
  • ethyl pyruvate
  • Carbon Tetrachloride
  • Matrix Metalloproteinases