Abstract
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.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Arachidonic Acids / metabolism
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Cannabinoid Receptor Modulators / metabolism*
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Carnitine O-Palmitoyltransferase / metabolism
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Cells, Cultured
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Coculture Techniques
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Diet, Fat-Restricted
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Disease Models, Animal
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Endocannabinoids*
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Ethanol
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Fatty Acid Synthases / metabolism
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Fatty Acids / metabolism
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Fatty Liver, Alcoholic / etiology
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Fatty Liver, Alcoholic / genetics
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Fatty Liver, Alcoholic / metabolism*
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Fatty Liver, Alcoholic / pathology
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Fatty Liver, Alcoholic / prevention & control
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Glycerides / metabolism
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Hepatocytes / metabolism
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Lipogenesis* / drug effects
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Lipogenesis* / genetics
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Lipoprotein Lipase / metabolism
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Liver / drug effects
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Liver / enzymology
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Liver / metabolism*
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Liver / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Oxidation-Reduction
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Paracrine Communication* / drug effects
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Paracrine Communication* / genetics
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Piperidines / pharmacology
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Pyrazoles / pharmacology
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Receptor, Cannabinoid, CB1 / antagonists & inhibitors
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Receptor, Cannabinoid, CB1 / genetics
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Receptor, Cannabinoid, CB1 / metabolism*
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Rimonabant
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Sterol Regulatory Element Binding Protein 1 / metabolism
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Up-Regulation
Substances
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Arachidonic Acids
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Cannabinoid Receptor Modulators
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Endocannabinoids
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Fatty Acids
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Glycerides
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Piperidines
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Pyrazoles
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Receptor, Cannabinoid, CB1
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Srebf1 protein, mouse
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Sterol Regulatory Element Binding Protein 1
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Ethanol
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glyceryl 2-arachidonate
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Carnitine O-Palmitoyltransferase
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Fatty Acid Synthases
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Lipoprotein Lipase
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Rimonabant