Bioactive compound reveals a novel function for ribosomal protein S5 in hepatic stellate cell activation and hepatic fibrosis.

Abstract

UNLABELLED:

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.

CONCLUSION:

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: Wei-Heng Xu, Hong-Gang Hu, Yuan Tian, Shao-Zhan Wang, Jie Li, Jian-Zhong Li, Xing Deng, Hui Qian, Lei Qiu, Zhen-Lin Hu, Qiu-Ye Wu, Yi-Feng Chai, Cheng Guo, Wei-Fen Xie, Jun-Ping Zhang
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 60 Issue 2 Pg. 648-60 (Aug 2014) ISSN: 1527-3350 [Electronic] United States
• PMID: 24668691 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by the American Association for the Study of Liver Diseases.

Chemical References

• 10-methylaminododecahydro-3a,7a-diazabenzo(de)anthracene-8-thione
• Alkaloids
• Heterocyclic Compounds, 4 or More Rings
• Quinolizines
• Ribosomal Proteins
• ribosomal protein S5
• Matrines

Topics

• Adenoviridae (genetics)
• Alkaloids (pharmacology)
• Animals
• Cell Line, Transformed
• Disease Models, Animal
• Gene Knockdown Techniques
• Hepatic Stellate Cells (drug effects, pathology, physiology)
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Liver Cirrhosis (drug therapy, pathology, physiopathology)
• Male
• Medicine, Chinese Traditional (methods)
• Myofibroblasts (drug effects, pathology, physiology)
• Phosphorylation (drug effects, physiology)
• Primary Cell Culture
• Quinolizines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Ribosomal Proteins (genetics, physiology)
• Signal Transduction (drug effects, physiology)
• Matrines