Membrane Cholesterol but Not Putative Receptors Mediates Anandamide-Induced Hepatocyte Apoptosis

Kamal Krishna Biswas, Krishna Pada Sarker, Kazuhiro Abeyama, Ko Ichi Kawahara, Satoshi Iino, Yasuharu Otsubo, Kazuhiko Saigo, Hiroyuki Izumi, Teruto Hashiguchi, Munekazu Yamakuchi, Kazuyo Yamaji, Ryujin Endo, Kazuyuki Suzuki, Hitoshi Imaizumi, Ikuro Maruyama

Research output: Contribution to journalArticlepeer-review

Abstract

The endogenous cannabinoid anandamide, a lipid mediator, induces various physiologic events such as vascular relaxation, inhibition of gap-junctions formation, tumor proliferation, neurologic analgesia, and apoptosis. Although increased concentration of anandamide in plasma has been implicated in pathophysiologic states including endotoxin-induced hypotension, the effects of anandamide on hepatocytes still remain unclear. In this study, we present evidence that plasma anandamide concentration is highly increased in severe hepatitis and cirrhosis patients. In addition, concentrations of anandamide within the pathophysiologic range potently induced apoptosis of hepatoma cell line (Hep G2) and primary hepatocytes, suggesting a possible link between increased anandamide level and hepatocyte damage. Anandamide-induced cell death was preceded by G0/G1 cell-cycle arrest, activation of proapoptotic signaling (i.e., p38 MAPK and JNK), and inhibition of antiapoptotic signaling (i.e., PKB/Akt) pathways. Moreover, anandamide increased susceptibility to oxidative stress-induced hepatocyte damage. In this context, methyl-β-cyclodextrin (MCD), a membrane cholesterol depletor, or mevastatin, an HMG-CoA reductase inhibitor, or N-acetyl cysteine, an antioxidant, potently inhibited the anandamide-induced proapoptotic events and cell death, whereas putative cannabinoid receptor antagonists did not exhibit an inhibitory effect on anandamide-induced cell death. Furthermore, binding assay using polymyxin beads revealed that anandamide could interact with cholesterol. In conclusion, our data suggest that cholesterol present in the cell membrane determines the fate of hepatocytes exposed to anandamide, possibly functioning as an anandamide receptor.

Original languageEnglish (US)
Pages (from-to)1167-1177
Number of pages11
JournalHepatology
Volume38
Issue number5
DOIs
StatePublished - Nov 2003

ASJC Scopus subject areas

  • Hepatology

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