Diabetes Center, Department of Anatomy, University of California, San Francisco, California.
Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, California.
Am J Physiol Endocrinol Metab. 2020 May 1;318(5):E655-E666. doi: 10.1152/ajpendo.00218.2019. Epub 2020 Feb 11.
Excessive alcohol consumption, including binge drinking, is a common cause of fatty liver disease. Binge drinking rapidly induces hepatic steatosis, an early step in the pathogenesis of chronic liver injury. Despite its prevalence, the process by which excessive alcohol consumption promotes hepatic lipid accumulation remains unclear. Alcohol exerts potent effects on the brain, including hypothalamic neurons crucial for metabolic regulation. However, whether or not the brain plays a role in alcohol-induced hepatic steatosis is unknown. In the brain, alcohol increases extracellular levels of adenosine, a potent neuromodulator, and previous work implicates adenosine signaling as being important for the development of alcoholic fatty liver disease. Acute alcohol exposure also increases both the activity of agouti-related protein (AgRP)-expressing neurons and AgRP immunoreactivity. Here, we show that adenosine receptor A signaling in the brain modulates the extent of alcohol-induced fatty liver in mice and that both the AgRP neuropeptide and the sympathetic nervous system are indispensable for hepatic steatosis induced by bingelike alcohol consumption. Together, these results indicate that the brain plays an integral role in alcohol-induced hepatic lipid accumulation and that central adenosine signaling, hypothalamic AgRP, and the sympathetic nervous system are crucial mediators of this process.
过量饮酒，包括酗酒，是导致脂肪肝的常见原因。酗酒会迅速引起肝脂肪变性，这是慢性肝损伤发病机制的早期步骤。尽管它很普遍，但过量饮酒促进肝脂质积累的过程仍不清楚。酒精对大脑有强烈的影响，包括对代谢调节至关重要的下丘脑神经元。然而，大脑是否在酒精引起的肝脂肪变性中起作用尚不清楚。在大脑中，酒精会增加外泌体中腺苷的水平，腺苷是一种有效的神经调节剂，之前的研究表明，腺苷信号对于酒精性脂肪肝的发展很重要。急性酒精暴露也会增加 AgRP 表达神经元的活性和 AgRP 免疫反应性。在这里，我们表明，大脑中的腺苷受体 A 信号调节了酒精诱导的小鼠脂肪肝的程度，而 AgRP 神经肽和交感神经系统对于类似酗酒引起的肝脂肪变性都是必不可少的。综上所述，这些结果表明，大脑在酒精诱导的肝脂质积累中起着不可或缺的作用，而中枢腺苷信号、下丘脑 AgRP 和交感神经系统是这一过程的关键介质。
