Leukamenin F suppresses liver fibrogenesis by inhibiting both hepatic stellate cell proliferation and extracellular matrix production.
OBJECTIVE
To investigate the inhibitory effect of the natural product Leukamenin F on liver fibrosis and explore its potential underlying mechanisms.


METHODS
Carbon tetrachloride (CCl(4))-treated mouse model in vivo and in hepatic stellate cells (HSC) in vitro were used. The effect on CCl(4)-induced liver fibrosis was studied using histochemical and biochemical analysis, while the inhibition on HSC was assessed using cell proliferation/apoptosis assay and collagen I production using real-time PCR. The inhibitory effects of Leukamenin F on Akt/mTOR/p70S6K and TGFbeta/Smad pathways was studied using Western blot and cell image analysis.


RESULTS
Leukamenin F (0.1-1 mg/kg, ip, q.d.x28) significantly reduced alpha-SMA and collagen specific Sirius red staining areas in CCl(4) -treated mouse livers. This compound at 1-2 micromol/L dose-dependently inhibited alpha-SMA expression, cell proliferation and type I procollagen mRNA expression in activated HSC. Furthermore it inhibited the Akt/mTOR/p70S6K pathway and suppressed TGFbeta -induced Smad2/Smad3 phosphorylation and nuclear translocation in HSC.


CONCLUSIONS
Our results demonstrated that Leukamenin F could attenuate CCl(4)-induced liver fibrogenesis in mice as an efficient inhibitor against both HSC proliferation and ECM production. This natural product provides a valuable structural hint for the development of anti-liver fibrosis reagents.
Liu
Qiong
Q
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
Wang
Xu
X
Zhang
Yu
Y
Li
Chen-jing
CJ
Hu
Li-hong
LH
Shen
Xu
X
D000199:Actins / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism
D000199:Actins; D024042:Collagen Type I; D004224:Diterpenes; D012333:RNA, Messenger; C544013:alpha-smooth muscle actin, mouse; C553167:leukamenin F; D002251:Carbon Tetrachloride