Bisdemethoxycurcumin induces apoptosis in Activated Hepatic Stellate Cells via cannabinoid receptor 2

Phil Jun Lee, Seung Je Woo, Jun Goo Jee, Sang Hyun Sung, Hong Pyo Kim

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Activated Hepatic Stellate Cells (HSCs), major fibrogenic cells in the liver, undergo apoptosis when liver injuries cease, which may contribute to the resolution of fibrosis. Bisdemethoxycurcumin (BDMC) is a natural derivative of curcumin with anti-inflammatory and anti-cancer activities. The therapeutic potential of BDMC in hepatic fibrosis has not been studied thus far in the context of the apoptosis in activated HSCs. In the current study, we compared the activities of BDMC and curcumin in the HSC-T6 cell line and demonstrated that BDMC relatively induced a potent apoptosis. BDMC-induced apoptosis was mediated by a combinatory inhibition of cytoprotective proteins, such as Bcl 2 and heme oxygenase-1 and increased generation of reactive oxygen species. Intriguingly, BDMC-induced apoptosis was reversed with co-treatment of sr144528, a cannabinoid receptor (CBR) 2 antagonist, which was confirmed with genetic downregulation of the receptor using siCBR2. Additionally, incubation with BDMC increased the formation of death-induced signaling complex in HSC-T6 cells. Treatment with BDMC significantly diminished total intracellular ATP levels and upregulated ATP inhibitory factor-1. Collectively, the results demonstrate that BDMC induces apoptosis in activated HSCs, but not in hepatocytes, by impairing cellular energetics and causing a downregulation of cytoprotective proteins, likely through a mechanism that involves CBR2.

Original languageEnglish
Pages (from-to)1277-1292
Number of pages16
JournalMolecules
Volume20
Issue number1
DOIs
StatePublished - 1 Jan 2015

Keywords

  • Adenosine triphosphate (ATP)
  • Bisdemethoxycurcumin (BDMC)
  • Cannabinoid receptor (CBR) 2
  • Curcumin
  • Death-inducing signaling complex (DISC)
  • Hepatic stellate cells (HSCs)
  • Liver fibrosis

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