title: Bioactive compound reveals a novel function for ribosomal protein S5 in hepatic stellate cell activation and hepatic fibrosis.
abstract: Liver fibrosis and its endstage, cirrhosis, represent a major public health problem worldwide. Activation of hepatic stellate cells (HSCs) is a central event in hepatic fibrosis. However, the proteins that control HSC activation are incompletely understood. Here we show that (6aS, 10S, 11aR, 11bR, 11cS)-10-methylamino-dodecahydro-3a, 7a-diaza-benzo [de]anthracene-8-thione (MASM) exhibits potent inhibitory activity against liver fibrosis in vitro and in vivo associated with the reduction of Akt phosphorylation. Furthermore, ribosomal protein S5 (RPS5) was identified as a direct target of MASM, which stabilized RPS5 in cultured HSCs and in the liver of experimental animals after dimethylnitrosamine (DMN) or bile duct ligation (BDL). Functional studies revealed that RPS5 could prevent HSC activation. RPS5 overexpression in HSCs resulted in Akt dephosphorylation at both Ser473 and Thr308, and led to subsequent dephosphorylation of GSK3β or P70S6K. Progression of DMN- and BDL-induced hepatic fibrosis was aggravated by Rps5 knockdown and alleviated by RPS5 overexpression, which correlated with the modulation of Akt phosphorylation and HSC number in the fibrotic livers. Moreover, RPS5 was substantially reduced in the transdifferentiated HSCs, experimental fibrotic livers, and human cirrhosis samples.
  
  
  CONCLUSIONS
  These results demonstrate that RPS5 is implicated in hepatic fibrogenesis and may represent a promising target for potential therapeutic intervention in liver fibrotic diseases.
authors.affiliation: College of Pharmacy, Second Military Medical University, Shanghai, China.
authors.forename: Wei-Heng
authors.initials: WH
authors.lastname: Xu
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Hu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.forename: Shao-Zhan
authors.initials: SZ
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Li
authors.forename: Xing
authors.initials: X
authors.lastname: Deng
authors.forename: Hui
authors.initials: H
authors.lastname: Qian
authors.forename: Lei
authors.initials: L
authors.lastname: Qiu
authors.forename: Zhen-Lin
authors.initials: ZL
authors.lastname: Hu
authors.forename: Qiu-Ye
authors.initials: QY
authors.lastname: Wu
authors.forename: Yi-Feng
authors.initials: YF
authors.lastname: Chai
authors.forename: Cheng
authors.initials: C
authors.lastname: Guo
authors.forename: Wei-Fen
authors.initials: WF
authors.lastname: Xie
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Zhang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000473:pathology* / Q000502:physiology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008516:Medicine, Chinese Traditional / Q000379:methods; D058628:Myofibroblasts / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D061251:Primary Cell Culture; D011807:Quinolizines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012269:Ribosomal Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000093842:Matrines
chemical_list: C000591649:10-methylaminododecahydro-3a,7a-diazabenzo(de)anthracene-8-thione; D000470:Alkaloids; D006576:Heterocyclic Compounds, 4 or More Rings; D011807:Quinolizines; D012269:Ribosomal Proteins; C030831:ribosomal protein S5; D000093842:Matrines