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The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species.
FASEB J. 2007 Sep; 21(11):2798-806.FJ

Abstract

The endocannabinoid system is an important regulator of hepatic fibrogenesis. In this study, we determined the effects of 2-arachidonoyl glycerol (2-AG) on hepatic stellate cells (HSCs), the main fibrogenic cell type in the liver. Culture-activated HSCs were highly susceptible to 2-AG-induced cell death with >50% cell death at 10 microM after 18 h of treatment. 2-AG-induced HSC death showed typical features of apoptosis such as PARP- and caspase 3-cleavage and depended on reactive oxygen species (ROS) formation. Confocal microscopy revealed mitochondria as primary site of ROS production and demonstrated mitochondrial depolarization and increased mitochondrial permeability after 2-AG treatment. 2-AG-induced cell death was independent of cannabinoid receptors but required the presence of membrane cholesterol. Primary hepatocytes were resistant to 2-AG-induced ROS induction and cell death but became susceptible after GSH depletion suggesting antioxidant defenses as a critical determinant of 2-AG sensitivity. Hepatic levels of 2-AG were significantly elevated in two models of experimental fibrogenesis and reached concentrations that are sufficient to induce death in HSCs. These findings suggest that 2-AG may act as an antifibrogenic mediator in the liver by inducing cell death in activated HSCs but not hepatocytes.

Authors+Show Affiliations

Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo 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

17440119

Citation

Siegmund, Sören V., et al. "The Endocannabinoid 2-arachidonoyl Glycerol Induces Death of Hepatic Stellate Cells Via Mitochondrial Reactive Oxygen Species." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 21, no. 11, 2007, pp. 2798-806.
Siegmund SV, Qian T, de Minicis S, et al. The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species. FASEB J. 2007;21(11):2798-806.
Siegmund, S. V., Qian, T., de Minicis, S., Harvey-White, J., Kunos, G., Vinod, K. Y., Hungund, B., & Schwabe, R. F. (2007). The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 21(11), 2798-806.
Siegmund SV, et al. The Endocannabinoid 2-arachidonoyl Glycerol Induces Death of Hepatic Stellate Cells Via Mitochondrial Reactive Oxygen Species. FASEB J. 2007;21(11):2798-806. PubMed PMID: 17440119.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species. AU - Siegmund,Sören V, AU - Qian,Ting, AU - de Minicis,Samuele, AU - Harvey-White,Judith, AU - Kunos,George, AU - Vinod,K Y, AU - Hungund,Basalingappa, AU - Schwabe,Robert F, Y1 - 2007/04/17/ PY - 2007/4/19/pubmed PY - 2007/10/12/medline PY - 2007/4/19/entrez SP - 2798 EP - 806 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J VL - 21 IS - 11 N2 - The endocannabinoid system is an important regulator of hepatic fibrogenesis. In this study, we determined the effects of 2-arachidonoyl glycerol (2-AG) on hepatic stellate cells (HSCs), the main fibrogenic cell type in the liver. Culture-activated HSCs were highly susceptible to 2-AG-induced cell death with >50% cell death at 10 microM after 18 h of treatment. 2-AG-induced HSC death showed typical features of apoptosis such as PARP- and caspase 3-cleavage and depended on reactive oxygen species (ROS) formation. Confocal microscopy revealed mitochondria as primary site of ROS production and demonstrated mitochondrial depolarization and increased mitochondrial permeability after 2-AG treatment. 2-AG-induced cell death was independent of cannabinoid receptors but required the presence of membrane cholesterol. Primary hepatocytes were resistant to 2-AG-induced ROS induction and cell death but became susceptible after GSH depletion suggesting antioxidant defenses as a critical determinant of 2-AG sensitivity. Hepatic levels of 2-AG were significantly elevated in two models of experimental fibrogenesis and reached concentrations that are sufficient to induce death in HSCs. These findings suggest that 2-AG may act as an antifibrogenic mediator in the liver by inducing cell death in activated HSCs but not hepatocytes. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/17440119/The_endocannabinoid_2_arachidonoyl_glycerol_induces_death_of_hepatic_stellate_cells_via_mitochondrial_reactive_oxygen_species_ L2 - https://doi.org/10.1096/fj.06-7717com DB - PRIME DP - Unbound Medicine ER -