Joint first author.
A histone deacetylase inhibitor, largazole, decreases liver fibrosis and angiogenesis by inhibiting transforming growth factor-β and vascular endothelial growth factor signalling
Version of Record online: 26 DEC 2012
© 2012 John Wiley & Sons A/S
Volume 33, Issue 4, pages 504–515, April 2013
How to Cite
Liver Int. 2013: 33: 504–515
Xiaojuan Sun and Zhiming Cai also contributed to this paper by performing work in the treatment of experimental liver fibrosis by largazole and by measuring the serum marker.
- Issue online: 12 MAR 2013
- Version of Record online: 26 DEC 2012
- Accepted manuscript online: 30 OCT 2012 07:52AM EST
- Manuscript Accepted: 22 OCT 2012
- Manuscript Received: 2 DEC 2011
- Hong Kong Research Grants Council. Grant Numbers: PolyU 5638/07M, PolyU 5040/10P
- Fong Shu Fook Tong Foundation
- Joyce M. Kuok Foundation
- The Hong Kong Polytechnic University. Grant Numbers: PolyU 5636/08M, PolyU 5634/09M
- Shenzhen Bureau of Science, Technology and Information. Grant Numbers: SY200806300179A, ZD200806180051A, ED200609150042A, JC200903160367A, GDSFC 10151805704000005
- The Science Technology and Innovation Committee of Shenzhen Municipality
- Peacock Plan for Product Research and Development
- NIH. Grant Number: DK56621
- hepatic stellate cells;
- liver fibrosis;
Background & Aims
Largazole is a novel histone deacetylase (HDAC) inhibitor. This study investigated the effects of largazole against liver fibrosis.
The in vitro effects of largazole were examined using hepatic stellate cells (HSCs). In vivo effects of largazole were studied using a mouse liver fibrotic model induced by CCl4.
Largazole augmented acetylation of histone H3 (H3) and histone H4 (H4) in HSCs. It directly inhibited the activation of HSCs owing to HDAC inhibitory activity as the antifibrotic effect of largazole was significantly decreased in cells with HDAC1, HDAC2 and HDAC3 knockdown. Largazole also induced apoptosis of HSCs. Largazole not only inhibited the expression of TGFβR2, but also reduced phosphorylation of Smad2 and Akt induced by TGF-β1. Largazole also inhibited the expression of vascular endothelial growth factor (VEGF) and its receptor. VEGF-induced proliferation of HSCs and activation of Akt and p38MAPK were also suppressed by largazole. In vivo, largazole reduced the expression of collagen I, α-smooth muscle actin and tissue inhibitor of metalloproteinase-1 in CCl4–induced fibrosis, and these antifibrotic effects were associated with increased acetylation of H3 and H4. Largazole also induced HSCs to undergo apoptosis in vivo, which was correlated with downregulation of bcl-2 and bcl-xL. Furthermore, largazole inhibited angiogenesis in vivo as evidenced by reduced expression of CD34, VEGF and VEGFR. In addition to its antifibrotic activity, the drug reduced inflammatory activity in CCl4-induced liver fibrosis.
Our findings revealed a novel role of largazole in the treatment of liver fibrosis. Through multiple mechanisms, largazole could be a potentially effective antifibrotic agent.