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* Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, USA;
Department of Medicine II, Medical Faculty at Mannheim, University of Heidelberg, Mannheim, Germany;
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA;
National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, Maryland, USA;
|| Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA; and
¶ Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York, USA
1Correspondence: Columbia University, Russ Berrie Pavillion, Rm. 415, 1150 St. Nicholas Ave, New York, NY, USA 10032. E-mail: rfs2102{at}columbia.edu
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 µM 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.—Siegmund, S. V., Qian, T., de Minicis, S., Harvey-White, J., Kunos, G., Vinod, K. Y., Hungund, B., Schwabe, R. F. The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species.
Key Words: ROS • 2-AG • HSC • hepatocyte • fibrosis
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