Activation of hepatic stellate cells (HSCs) is a pivotal event leading to extracellular matrix (ECM) overproduction during hepatic fibrogenesis. Compelling evidence indicates that cannabinoid receptors (CBRs) play an important role in chronic liver disease. Antagonism of hepatic CBR type 1 (CBR₁) could be novel therapeutic strategies for liver fibrosis. Our previous studies have demonstrated that curcumin has potent antifibrotic activity, but the mechanisms remain to be elucidated. The current work was to examine the curcumin effect on CBRs system and its relevance to inhibition of ECM expression in HSCs. Our in vivo data demonstrated that curcumin ameliorated fibrotic injury, and downregulated CBR₁ but upregulated CBR₂ at both mRNA and protein levels in rat fibrotic liver caused by carbon tetrachloride. The subsequent in vitro investigations showed that curcumin reduced the mRNA and protein abundance of CBR₁ in cultured HSCs and decreased the expression of three critical ECM proteins. Further analyses revealed that CBR₁ agonist abrogated the curcumin inhibition of ECM expression, but CBR₁ antagonist mimicked and reinforced the curcumin effects. Autodock simulations predicted that curcumin could bind to CBR₁ with two hydrogen bonds. Collectively, our current studies revealed that curcumin reduction of liver fibrosis was associated with modulation of CBRs system and that antagonism of CBR₁ contributed to curcumin inhibition of ECM expression.
© 2013 Published by Elsevier B.V.

PMID:

 

24076327

 

[PubMed – as supplied by publisher]