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Anandamide induces necrosis in primary hepatic stellate cells.
Hepatology. 2005 May; 41(5):1085-95.Hep

Abstract

The endogenous cannabinoid anandamide (AEA) is a lipid mediator that blocks proliferation and induces apoptosis in many cell types. Although AEA levels are elevated in liver fibrosis, its role in fibrogenesis remains unclear. This study investigated effects of AEA in primary hepatic stellate cells (HSCs). Anandamide blocked HSC proliferation at concentrations of 1 to 10 micromol/L but did not affect HSC proliferation or activation at nanomolar concentrations. At higher concentrations (25-100 micromol/L), AEA rapidly and dose-dependently induced cell death in primary culture-activated and in vivo-activated HSCs, with over 70% cell death after 4 hours at 25 micromol/L. In contrast to treatment with Fas ligand or gliotoxin, AEA-mediated death was caspase independent and showed typical features of necrosis such as rapid adenosine triphosphate depletion and propidium iodide uptake. Anandamide-induced reactive oxygen species (ROS) formation, and an increase in intracellular Ca(2+). Pretreatment with the antioxidant glutathione or Ca(2+)-chelation attenuated AEA-induced cell death. Although the putative endocannabinoid receptors CB1, CB2, and VR1 were expressed in HSCs, specific receptor blockade failed to block cell death. Depletion of membrane cholesterol by methyl-beta-cyclodextrin inhibited AEA binding, blocked ROS formation and intracellular Ca(2+)-increase, and prevented cell death. In primary hepatocytes, AEA showed significantly lower binding and failed to induce cell death even after prolonged treatment. In conclusion, AEA efficiently induces necrosis in activated HSCs, an effect that depends on membrane cholesterol and a subsequent increase in intracellular Ca(2+) and ROS. The anti-proliferative effects and the selective killing of HSCs, but not hepatocytes, indicate that AEA may be used as a potential anti-fibrogenic tool.

Authors+Show Affiliations

Department of Medicine, Columbia University, College of Physicians & Surgeons, New York, NY 10032, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15841466

Citation

Siegmund, Sören V., et al. "Anandamide Induces Necrosis in Primary Hepatic Stellate Cells." Hepatology (Baltimore, Md.), vol. 41, no. 5, 2005, pp. 1085-95.
Siegmund SV, Uchinami H, Osawa Y, et al. Anandamide induces necrosis in primary hepatic stellate cells. Hepatology. 2005;41(5):1085-95.
Siegmund, S. V., Uchinami, H., Osawa, Y., Brenner, D. A., & Schwabe, R. F. (2005). Anandamide induces necrosis in primary hepatic stellate cells. Hepatology (Baltimore, Md.), 41(5), 1085-95.
Siegmund SV, et al. Anandamide Induces Necrosis in Primary Hepatic Stellate Cells. Hepatology. 2005;41(5):1085-95. PubMed PMID: 15841466.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anandamide induces necrosis in primary hepatic stellate cells. AU - Siegmund,Sören V, AU - Uchinami,Hiroshi, AU - Osawa,Yosuke, AU - Brenner,David A, AU - Schwabe,Robert F, PY - 2005/4/21/pubmed PY - 2005/6/2/medline PY - 2005/4/21/entrez SP - 1085 EP - 95 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 41 IS - 5 N2 - The endogenous cannabinoid anandamide (AEA) is a lipid mediator that blocks proliferation and induces apoptosis in many cell types. Although AEA levels are elevated in liver fibrosis, its role in fibrogenesis remains unclear. This study investigated effects of AEA in primary hepatic stellate cells (HSCs). Anandamide blocked HSC proliferation at concentrations of 1 to 10 micromol/L but did not affect HSC proliferation or activation at nanomolar concentrations. At higher concentrations (25-100 micromol/L), AEA rapidly and dose-dependently induced cell death in primary culture-activated and in vivo-activated HSCs, with over 70% cell death after 4 hours at 25 micromol/L. In contrast to treatment with Fas ligand or gliotoxin, AEA-mediated death was caspase independent and showed typical features of necrosis such as rapid adenosine triphosphate depletion and propidium iodide uptake. Anandamide-induced reactive oxygen species (ROS) formation, and an increase in intracellular Ca(2+). Pretreatment with the antioxidant glutathione or Ca(2+)-chelation attenuated AEA-induced cell death. Although the putative endocannabinoid receptors CB1, CB2, and VR1 were expressed in HSCs, specific receptor blockade failed to block cell death. Depletion of membrane cholesterol by methyl-beta-cyclodextrin inhibited AEA binding, blocked ROS formation and intracellular Ca(2+)-increase, and prevented cell death. In primary hepatocytes, AEA showed significantly lower binding and failed to induce cell death even after prolonged treatment. In conclusion, AEA efficiently induces necrosis in activated HSCs, an effect that depends on membrane cholesterol and a subsequent increase in intracellular Ca(2+) and ROS. The anti-proliferative effects and the selective killing of HSCs, but not hepatocytes, indicate that AEA may be used as a potential anti-fibrogenic tool. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/15841466/Anandamide_induces_necrosis_in_primary_hepatic_stellate_cells_ L2 - https://doi.org/10.1002/hep.20667 DB - PRIME DP - Unbound Medicine ER -