Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver

• Published in: Cell metabolism Vol. 7; no. 3; pp. 227 - 235
• Main Authors: Jeong, Won-il, Osei-Hyiaman, Douglas, Park, Ogyi, Liu, Jie, Bátkai, Sándor, Mukhopadhyay, Partha, Horiguchi, Norio, Harvey-White, Judith, Marsicano, Giovanni, Lutz, Beat, Gao, Bin, Kunos, George
• Format: Journal Article
• Language: English
• Published: United States 01.03.2008
• Subjects: Animals; Arachidonic Acids - metabolism; Cannabinoid Receptor Modulators - metabolism; Carnitine O-Palmitoyltransferase - metabolism; Cells, Cultured; Coculture Techniques; Diet, Fat-Restricted; Disease Models, Animal; Endocannabinoids; Ethanol; Fatty Acid Synthases - metabolism; Fatty Acids - metabolism; Fatty Liver, Alcoholic - etiology; Fatty Liver, Alcoholic - genetics; Fatty Liver, Alcoholic - metabolism; Fatty Liver, Alcoholic - pathology; Fatty Liver, Alcoholic - prevention & control; Glycerides - metabolism; Hepatocytes - metabolism; Lipogenesis - drug effects; Lipogenesis - genetics; Lipoprotein Lipase - metabolism; Liver - drug effects; Liver - enzymology; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxidation-Reduction; Paracrine Communication - drug effects; Paracrine Communication - genetics; Piperidines - pharmacology; Pyrazoles - pharmacology; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - genetics; Receptor, Cannabinoid, CB1 - metabolism; Sterol Regulatory Element Binding Protein 1 - metabolism; Up-Regulation
• ISSN: 1550-4131
• DOI: 10.1016/j.cmet.2007.12.007

Alcohol-induced fatty liver, a major cause of morbidity, has been attributed to enhanced hepatic lipogenesis and decreased fat clearance of unknown mechanism. Here we report that the steatosis induced in mice by a low-fat, liquid ethanol diet is attenuated by concurrent blockade of cannabinoid CB1 receptors. Global or hepatocyte-specific CB1 knockout mice are resistant to ethanol-induced steatosis and increases in lipogenic gene expression and have increased carnitine palmitoyltransferase 1 activity, which, unlike in controls, is not reduced by ethanol treatment. Ethanol feeding increases the hepatic expression of CB1 receptors and upregulates the endocannabinoid 2-arachidonoylglycerol (2-AG) and its biosynthetic enzyme diacylglycerol lipase beta selectively in hepatic stellate cells. In control but not CB1 receptor-deficient hepatocytes, coculture with stellate cells from ethanol-fed mice results in upregulation of CB1 receptors and lipogenic gene expression. We conclude that paracrine activation of hepatic CB1 receptors by stellate cell-derived 2-AG mediates ethanol-induced steatosis through increasing lipogenesis and decreasing fatty acid oxidation.