Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver.
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.
Jeong
Won-il
WI
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Osei-Hyiaman
Douglas
D
Park
Ogyi
O
Liu
Jie
J
Bátkai
Sándor
S
Mukhopadhyay
Partha
P
Horiguchi
Norio
N
Harvey-White
Judith
J
Marsicano
Giovanni
G
Lutz
Beat
B
Gao
Bin
B
Kunos
George
G
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D018752:Diet, Fat-Restricted; D004195:Disease Models, Animal; D063388:Endocannabinoids; D000431:Ethanol; D064429:Fatty Acid Synthases / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005235:Fatty Liver, Alcoholic / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D005989:Glycerides / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008071:Lipoprotein Lipase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D019899:Paracrine Communication / Q000187:drug effects / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077285:Rimonabant; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D015854:Up-Regulation
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005227:Fatty Acids; D005989:Glycerides; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D000431:Ethanol; C094503:glyceryl 2-arachidonate; D002334:Carnitine O-Palmitoyltransferase; D064429:Fatty Acid Synthases; D008071:Lipoprotein Lipase; D000077285:Rimonabant