Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver.
Cell Metabolism. 2008-03-01; 7(3): 227-235
DOI: 10.1016/j.cmet.2007.12.007
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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.
Author information:
(1)Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and
Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Comment in
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.
DOI: 10.1016/j.cmet.2007.12.007
PMID: 18316028 [Indexed for MEDLINE]