Leukamenin F suppresses liver fibrogenesis by inhibiting both hepatic stellate cell proliferation and extracellular matrix production.

Abstract

AIM:

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.

CONCLUSION:

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.

• Authors: Qiong Liu, Xu Wang, Yu Zhang, Chen-jing Li, Li-hong Hu, Xu Shen
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 31 Issue 7 Pg. 839-48 (Jul 2010) ISSN: 1745-7254 [Electronic] United States
• PMID: 20562900 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Collagen Type I
• Diterpenes
• RNA, Messenger
• alpha-smooth muscle actin, mouse
• leukamenin F
• Carbon Tetrachloride

Topics

• Actins (drug effects, genetics)
• Animals
• Carbon Tetrachloride (toxicity)
• Cell Proliferation (drug effects)
• Collagen Type I (drug effects, genetics)
• Disease Models, Animal
• Diterpenes (administration & dosage, pharmacology)
• Dose-Response Relationship, Drug
• Extracellular Matrix (drug effects, metabolism)
• Gene Expression Regulation (drug effects)
• Hepatic Stellate Cells (drug effects, metabolism)
• Liver Cirrhosis (physiopathology, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Polymerase Chain Reaction
• RNA, Messenger (metabolism)