A brain-liver circuit in regulation of alcoholic liver disease

描述（由申请人提供）：肝病是美国疾病和死亡的主要原因之一。过量饮酒是肝损伤的主要危险因素，超过200万美国人患有酒精引起的肝病。虽然肝脂肪变性是一个普遍的表型酗酒者，其发展的机制还没有得到很好的理解。目前认为，酒精直接作用于肝脏，改变脂质代谢，导致肝脂肪变性的发展。我们的实验室最近描绘了一个新的脑-肝回路，在生理条件下，如饥饿和肥胖，调节非酒精性脂肪肝。我们发现，下丘脑神经肽Agouti相关蛋白（AGRP）在大脑中的行为，以抑制肝交感神经活动和刺激脂质合成。AGRP是发生在饥饿和肥胖中的肝脂肪变性的发展所必需的。有趣的是，乙醇给药刺激小鼠下丘脑中的Agrp表达，并且AGRP缺陷小鼠对乙醇诱导的肝脂肪变性的发展具有抗性，而不改变喂养和体重。这项提议的目的是检验乙醇诱导肝脂肪变性的假设， 至少部分通过刺激下丘脑Agrp表达，导致肝交感神经活性的改变和肝脂肪变性的发展。酒精对Agrp表达和肝脂肪变性影响的信号机制将被确定。我们将进一步研究在乙醇诱导的肝脂肪变性中调节肝交感神经活性的重要性。最后，我们将评估针对Agrp的RNA干扰的治疗潜力， 减轻慢性加酗酒引起的肝损伤。综上所述，本提案中概述的实验将定义乙醇诱导的肝脂肪变性病因学的新机制，并将探索治疗酒精性肝病的新策略。

DESCRIPTION (provided by applicant): Liver disease is one of the leading causes of illness and death in the United States. Excessive alcohol consumption is a major risk factor for liver damage, and more than 2 million Americans suffer from liver disease caused by alcohol. Although hepatic steatosis is a prevalent phenotype among heavy alcohol drinkers, the mechanisms underlying its development are not well understood. It is currently thought that alcohol acts directly on the liver to alter lipid metabolism leading to development of hepatic steatosis. Our lab has recently delineated a novel brain-liver circuit in regulation of non-alcoholc fatty liver under physiologic conditions such as starvation and obesity. We show that hypothalamic neuropeptide Agouti-related protein (AGRP) acts in the brain to suppress hepatic sympathetic activity and to stimulate lipid synthesis. AGRP is required for the development of hepatic steatosis that occurs in starvation and obesity. Intriguingly, ethanol administration stimulates Agrp expression in the mouse hypothalamus, and AGRP-deficient mice are resistant to development of ethanol-induced hepatic steatosis without alteration of feeding and body weight. The goal of this proposal is to test the hypothesis that ethanol induces hepatic steatosis, at least in part, by stimulation of hypothalamic Agrp expression, resulting in alteration of hepati sympathetic activity and development of hepatic steatosis. Signaling mechanisms underlying alcohol's effects on Agrp expression and hepatic steatosis will be determined. We will further investigate the importance of modulating hepatic sympathetic activity in ethanol-induced hepatic steatosis. Finally, we will evaluate the therapeutic potentials of RNA-interference against Agrp in alleviating liver injury induced by chronic plus binge alcohol consumption. Taken together, experiments outlined in this proposal will define a new mechanism that underlies the etiology of ethanol- induced hepatic steatosis and will explore a novel strategy to treat alcoholic liver diseases.