Brown fat activation mitigates alcohol-induced liver steatosis and injury in mice
Brown fat activation mitigates alcohol-induced liver steatosis and injury in mice
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DOI：
10.1172/jci124376
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发表时间：
2019-06-03
影响因子：
15.9
通讯作者：
Rui, Liangyou
中科院分区：
文献类型：
--
作者：
Shen, Hong;Jiang, Lin;Rui, Liangyou
长期饮酒会导致肝损伤、炎症和纤维化，从而增加发病率和死亡率。奇怪的是，适度饮酒被认为可以改善新陈代谢，但其潜在机制仍然难以捉摸。在这里，我们已经确定了一个肝保护脑/棕色脂肪组织（BAT）/肝轴。酒精消费或直接酒精管理到大脑刺激下丘脑神经回路和交感神经支配BAT和显着增加BAT解偶联蛋白1（Ucp 1）的表达和活性的BAT-交感神经依赖性的方式。BAT和米色脂肪氧化脂肪酸，为Ucp 1介导的产热提供燃料，从而抑制脂质运输到肝脏。BAT还分泌几种脂肪因子，包括脂联素，其抑制肝细胞损伤和死亡。在雄性和雌性小鼠中，Ucp 1基因缺失显著增加了酒精诱导的肝脏脂肪变性、损伤、炎症和纤维化。相反，通过冷暴露激活BAT和米色脂肪抑制了酒精性肝病的发展。我们的研究结果揭示了一个未被识别的大脑酒精感应/交感神经/BAT/肝轴，抵消肝脏脂肪变性和损伤。
Chronic alcohol consumption causes liver injury, inflammation, and fibrosis, thereby increasing morbidity and mortality. Paradoxically, modest drinking is believed to confer metabolic improvement, but the underlying mechanism remains elusive. Here, we have identified a hepatoprotective brain/brown adipose tissue (BAT)/liver axis. Alcohol consumption or direct alcohol administration into the brain stimulated hypothalamic neural circuits and sympathetic nerves innervating BAT and dramatically increased BAT uncoupling protein 1 (Ucp1) expression and activity in a BAT-sympathetic nerve-dependent manner. BAT and beige fat oxidized fatty acids to fuel Ucp1-mediated thermogenesis, thereby inhibiting lipid trafficking into the liver. BAT also secreted several adipokines, including adiponectin, which suppressed hepatocyte injury and death. Genetic deletion of Ucp1 profoundly augmented alcohol-induced liver steatosis, injury, inflammation, and fibrosis in male and female mice. Conversely, activation of BAT and beige fat through cold exposure suppressed alcoholic liver disease development. Our results unravel an unrecognized brain alcohol-sensing/sympathetic nerve/BAT/liver axis that counteracts liver steatosis and injury.