Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver
Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver
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DOI：
10.1016/j.cmet.2007.12.007
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发表时间：
2008-03-01
期刊：
影响因子：
29
通讯作者：
Kunos, George
中科院分区：
文献类型：
--
作者：
Jeong, Won-il;Osei-Hyiaman, Douglas;Kunos, George
酒精引起的脂肪肝是发病的一个主要原因，其归因于肝脏脂肪生成增强和脂肪清除减少，但机制未知。在这里，我们报告说，通过同时阻断大麻素 CB1 受体，可以减轻低脂液体乙醇饮食引起的小鼠脂肪变性。整体或肝细胞特异性 CB1 敲除小鼠对乙醇诱导的脂肪变性有抵抗力，脂肪生成基因表达增加，肉毒碱棕榈酰转移酶 1 活性增加，与对照组不同，乙醇处理不会降低该活性。饲喂乙醇会增加肝星状细胞中 CB1 受体的肝脏表达，并选择性上调内源性大麻素 2-花生四烯酰甘油 (2-AG) 及其生物合成酶二酰基甘油脂肪酶 β。在对照肝细胞中，但在缺乏 CB1 受体的肝细胞中，与乙醇喂养小鼠的星状细胞共培养会导致 CB1 受体和脂肪生成基因表达上调。我们得出的结论是，星状细胞来源的 2-AG 旁分泌激活肝 CB1 受体，通过增加脂肪生成和减少脂肪酸氧化来介导乙醇诱导的脂肪变性。
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.