Jeong Won-il, Osei-Hyiaman Douglas, Park Ogyi, Liu Jie, Bátkai Sándor, Mukhopadhyay Partha, Horiguchi Norio, Harvey-White Judith, Marsicano Giovanni, Lutz Beat, Gao Bin, Kunos George
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):227-35. doi: 10.1016/j.cmet.2007.12.007.
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.
酒精性脂肪肝是发病的主要原因，其归因于肝脏脂肪生成增强和脂肪清除减少，而机制不明。在此我们报告，低脂液体乙醇饮食诱导的小鼠脂肪变性可通过同时阻断大麻素CB1受体而减轻。全身性或肝细胞特异性CB1基因敲除小鼠对乙醇诱导的脂肪变性具有抗性，脂肪生成基因表达增加，肉碱棕榈酰转移酶1活性增强，与对照组不同，乙醇处理不会降低其活性。喂食乙醇会增加CB1受体的肝脏表达，并选择性地上调肝星状细胞中内源性大麻素2-花生四烯酸甘油酯（2-AG）及其生物合成酶二酰基甘油脂肪酶β。在对照肝细胞而非CB1受体缺陷型肝细胞中，与喂食乙醇小鼠的星状细胞共培养会导致CB1受体上调和脂肪生成基因表达增加。我们得出结论，星状细胞衍生的2-AG对肝脏CB1受体的旁分泌激活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。
