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

W Jeong, D Osei-Hyiaman, O Park, J Liu, S Bátkai… - Cell metabolism, 2008 - cell.com
W Jeong, D Osei-Hyiaman, O Park, J Liu, S Bátkai, P Mukhopadhyay, N Horiguchi…
Cell metabolism, 2008cell.com
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 CB 1 receptors. Global or hepatocyte-specific CB 1 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 …
Summary
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.
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