Paracrine Activation of Hepatic CB1 Receptors by Stellate Cell-Derived Endocannabinoids Mediates Alcoholic Fatty Liver

6533b851fe1ef96bd12a8e78

RESEARCH PRODUCT

Paracrine Activation of Hepatic CB1 Receptors by Stellate Cell-Derived Endocannabinoids Mediates Alcoholic Fatty Liver

Douglas Osei-hyiaman George Kunos Jie Liu Bin Gao Giovanni Marsicano Ogyi Park Beat Lutz Sandor Batkai Partha Mukhopadhyay Won-il Jeong Norio Horiguchi Judith Harvey-white

subject

Male medicine.medical_specialty Physiology HUMDISEASE Arachidonic Acids Glycerides Mice Carnitine palmitoyltransferase 1 Piperidines Receptor Cannabinoid CB1 Internal medicine Cannabinoid Receptor Modulators Paracrine Communication medicine Animals Receptor Diet Fat-Restricted Molecular Biology Cells Cultured Mice Knockout Carnitine O-Palmitoyltransferase Ethanol Chemistry Lipogenesis Fatty Acids Fatty liver Cell Biology medicine.disease Endocannabinoid system Coculture Techniques Up-Regulation Mice Inbred C57BL Disease Models Animal Lipoprotein Lipase Endocrinology Liver Lipogenesis Hepatocytes Hepatic stellate cell Pyrazoles lipids (amino acids peptides and proteins)Alcoholic fatty liver Fatty Acid Synthases Rimonabant Steatosis Sterol Regulatory Element Binding Protein 1 Oxidation-Reduction Endocannabinoids Fatty Liver Alcoholic

description

SummaryAlcohol-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 β 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.

year	journal	country	edition	language
2008-03-01	Cell Metabolism

https://doi.org/10.1016/j.cmet.2007.12.007