Naringin in Ganshuang Granule Suppresses Activation of Hepatic Stellate Cells for Anti-Fibrosis Effect by Inhibition of Mammalian Target of Rapamycin

J Cell Mol Med. 2017 Mar;21(3):500-509. doi: 10.1111/jcmm.12994. Epub 2016 Sep 30.

Abstract

A previous study has demonstrated that Ganshuang granule (GSG) plays an anti-fibrotic role partially by deactivation of hepatic stellate cells (HSCs). In HSCs activation, mammalian target of rapamycin (mTOR)-autophagy plays an important role. We attempted to investigate the role of mTOR-autophagy in anti-fibrotic effect of GSG. The cirrhotic mouse model was prepared to demonstrate the anti-fibrosis effect of GSG. High performance liquid chromatography (HPLC) analyses were used to identify the active component of GSG. The primary mouse HSCs were isolated and naringin was added into activated HSCs to observe its anti-fibrotic effect. 3-methyladenine (3-MA) and Insulin-like growth factor-1 (IGF-1) was added, respectively, into fully activated HSCs to explore the role of autophagy and mTOR. GSG played an anti-fibrotic role through deactivation of HSCs in cirrhotic mouse model. The concentration of naringin was highest in GSG by HPLC analyses and naringin markedly suppressed HSCs activation in vitro, which suggested that naringin was the main active component of GSG. The deactivation of HSCs caused by naringin was not because of the autophagic activation but mTOR inhibition, which was supported by the following evidence: first, naringin induced autophagic activation, but when autophagy was blocked by 3-MA, deactivation of HSCs was not attenuated or reversed. Second, naringin inhibited mTOR pathway, meanwhile when mTOR was activated by IGF-1, deactivation of HSCs was reversed. In conclusion, we have demonstrated naringin in GSG suppressed activation of HSCs for anti-fibrosis effect by inhibition of mTOR, indicating a potential therapeutic application for liver cirrhosis.

Keywords: autophagy; hepatic stellate cells; mammalian target of rapamycin; naringin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / metabolism
  • Animals
  • Autophagy / drug effects
  • Cells, Cultured
  • Drugs, Chinese Herbal / pharmacology*
  • Fibrosis / drug therapy*
  • Fibrosis / metabolism
  • Flavanones / pharmacology*
  • Hepatic Stellate Cells / drug effects*
  • Hepatic Stellate Cells / metabolism
  • Insulin-Like Growth Factor I / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / metabolism
  • Male
  • Medicine, Chinese Traditional / methods
  • Mice
  • Mice, Inbred BALB C
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Drugs, Chinese Herbal
  • Flavanones
  • 3-methyladenine
  • Insulin-Like Growth Factor I
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Adenine
  • naringin