Statins improve NASH via inhibition of RhoA and Ras

Robert Schierwagen, Lara Maybuechen, Kanishka Hittatiya, Sabine Klein, Frank E. Uschner, Tarcio T. Braga, Bernardo S. Franklin, Georg Nickenig, Christian P. Strassburg, Jogchum Plat, Tilman Sauerbruch, Eicke Latz, Dieter Luetjohann, Sebastian Zimmer, Jonel Trebicka*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

35 Citations (Web of Science)

Abstract

Nonalcoholic steatohepatitis (NASH), especially as part of the metabolic syndrome (MS), is an increasing burden in Western countries. Statins are already used in MS and seem to be beneficial in liver diseases. The aim of this study was to investigate the molecular mechanisms underlying pleiotropic effects on small GTPases of statins in NASH. NASH within MS was induced in 12-wk-old apoE(-/-) mice after 7 wk of Western diet (NASH mice). Small GTPases were inhibited by activated simvastatin (SMV), NSC23766 (NSC), or Clostridium sordellii lethal toxin (LT) by using subcutaneous osmotic minipumps. Hepatic steatosis, inflammation, and fibrosis were assessed by histology, Western blot, and RT-PCR measurements of cholesterol and hydroxyproline content. SMV treatment significantly decreased hepatic inflammation and fibrosis, but had no significant effect on steatosis and hepatic cholesterol content in NASH. SMV blunted fibrosis due to inhibition of both RhoA/Rho kinase and Ras/ERK pathways. Interestingly, inhibition of RAC1 and Ras (by LT) failed to decrease fibrosis to the same extent. Inhibition of RAC1 (by NSC) showed no significant effect at all. Inhibition of RhoA and Ras downstream signaling by statins is responsible for the beneficial hepatic effects in NASH.
Original languageEnglish
Pages (from-to)G724-G733
JournalAmerican Journal of Physiology-Gastrointestinal and Liver Physiology
Volume311
Issue number4
DOIs
Publication statusPublished - 1 Oct 2016

Keywords

  • NASH
  • liver fibrosis
  • statins
  • apoE
  • Western diet
  • GTPase

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