title: Statins improve NASH via inhibition of RhoA and Ras.
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.
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Robert
authors.identifier: 0000-0002-2195-3666
authors.initials: R
authors.lastname: Schierwagen
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Lara
authors.initials: L
authors.lastname: Maybüchen
authors.affiliation: Institute of Pathology, University of Bonn, Bonn, Germany.
authors.forename: Kanishka
authors.initials: K
authors.lastname: Hittatiya
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Klein
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Frank E
authors.initials: FE
authors.lastname: Uschner
authors.affiliation: Institute of Innate Immunity, University of Bonn, Bonn, Germany.
authors.forename: Tarcio T
authors.initials: TT
authors.lastname: Braga
authors.affiliation: Institute of Innate Immunity, University of Bonn, Bonn, Germany.
authors.forename: Bernardo S
authors.initials: BS
authors.lastname: Franklin
authors.affiliation: Department of Internal Medicine II, University of Bonn, Bonn, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Strassburg
authors.affiliation: Department of Human Biology, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Jogchum
authors.initials: J
authors.lastname: Plat
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.affiliation: Institute of Innate Immunity, University of Bonn, Bonn, Germany.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany; and.
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.affiliation: Institute of Innate Immunity, University of Bonn, Bonn, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zimmer
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany; jonel.trebicka@ukb.uni-bonn.de.|Faculty of Health Sciences, Odense University Hospital, Odense, Denmark.
authors.forename: Jonel
authors.initials: J
authors.lastname: Trebicka
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D066273:Diet, Western; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use*; D018631:ras Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D019821:Simvastatin; D018631:ras Proteins; D020742:rhoA GTP-Binding Protein
keywords: GTPase; NASH; Western diet; apoE; liver fibrosis; statins