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 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.