Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver.
Cell Metabolism. 2008-03-01; 7(3): 227-235
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1. Cell Metab. 2008 Mar;7(3):227-35. doi: 10.1016/j.cmet.2007.12.007.
Paracrine activation of hepatic CB1 receptors by stellate cell-derived
endocannabinoids mediates alcoholic fatty liver.
Jeong WI(1), Osei-Hyiaman D, Park O, Liu J, Bátkai S, Mukhopadhyay P, Horiguchi
N, Harvey-White J, Marsicano G, Lutz B, Gao B, Kunos G.
(1)Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and
Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Metab. 2008 Mar;7(3):187-8.
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.
PMID: 18316028 [Indexed for MEDLINE]