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首页> 外文期刊>The FASEB Journal >The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species
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The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species

机译：The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species

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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 mu M 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.

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