Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 721, Issue 1-3, Pages 133-140Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2013.09.042
Keywords
Liver fibrosis; Hepatic stellate cell; Curcumin; Cannabinoid receptor; Extracellular matrix
Categories
Funding
- National Natural Science Foundation of China [81270514, 30873424]
- Doctoral Discipline Foundation of the Ministry of Education of China [20103 237110010]
- Jiangsu Natural Science Foundation [BK2008456]
- Project for Jiangsu Basic Research Natural Science Foundation [BK2012528]
- Project for Supporting Jiangsu Provincial Talents in Six Fields [2009-B-010]
- Open Program of Jiangsu Key Laboratory of Integrated Acupuncture and Drugs [KJA200801]
- Open Project Program of the National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine [2011ZYX4-008]
- Eleven-Five National Science and Technology Supporting Program [2008BAI51B02]
- Priority Academic Program Development of Jiangsu Higher Education Institutions [2011-137]
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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 a novel therapeutic strategy 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 in HSCs. (C) 2013 Elsevier B.V. All rights reserved
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