title: Ursolic acid ameliorates hepatic fibrosis in the rat by specific induction of apoptosis in hepatic stellate cells.
abstract: OBJECTIVE
  Specific induction of cell death in activated hepatic stellate cells (HSCs) is a promising therapeutic strategy for hepatic fibrosis. In this study, we evaluated the cell-killing effect of ursolic acid (UA), a pentacyclic triterpenoid, in activated HSCs both in vitro and in vivo.
  
  
  METHODS
  Culture-activated rat HSCs were treated with UA (0-40μM), and the mechanisms of cell death were evaluated. The cell killing effect of UA on activated HSCs in rats chronically treated with thioacetamide (TAA) was detected by dual staining of TdT-mediated dUTP nick-end labeling (TUNEL) and smooth muscle α-actin (αSMA) immunohistochemistry, and resolution of hepatic fibrosis was evaluated. Further, the protective effects of UA on progression of hepatic fibrosis caused by TAA and bile duct ligation (BDL) were evaluated.
  
  
  RESULTS
  UA induced apoptotic cell death in culture-activated HSCs, but not in isolated hepatocytes and quiescent HSCs. Mitochodrial permeability transition (MPT) preceded the cleavage of caspase-3 and -9 following UA treatment. UA also decreased phosphorylation levels of Akt, and diminished nuclear localization of NFκB in these cells. In rats pretreated with TAA for 6weeks, a single injection of UA induced remarkable increases in TUNEL- and αSMA-dual-positive cells in 24h, and significant regression of hepatic fibrosis within 48h. Moreover, UA ameliorated hepatic fibrogenesis caused by both chronic TAA administration and BDL.
  
  
  CONCLUSIONS
  UA ameliorated experimental hepatic fibrosis most likely through specific induction of apoptosis in activated HSCs. It is therefore postulated that UA is a potential therapeutic reagent for resolution of hepatic fibrosis.
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ikejima
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kon
authors.forename: Kumiko
authors.initials: K
authors.lastname: Arai
authors.forename: Tomonori
authors.initials: T
authors.lastname: Aoyama
authors.forename: Kyoko
authors.initials: K
authors.lastname: Okumura
authors.forename: Wataru
authors.initials: W
authors.lastname: Abe
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Sato
authors.forename: Sumio
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001652:Bile Ducts; D018450:Disease Progression; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D008026:Ligation; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013853:Thioacetamide / Q000633:toxicity; D014315:Triterpenes / Q000627:therapeutic use*; D000097245:Ursolic Acid
chemical_list: D016328:NF-kappa B; D051057:Proto-Oncogene Proteins c-akt; D013853:Thioacetamide; D014315:Triterpenes; D000097245:Ursolic Acid