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风险因素，超过200万美国人患有由酒精引起的肝脏疾病。尽管肝脂肪变性是重度饮酒者中普遍存在的表型，但其发展的机制尚不清楚。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。我们的实验室最近描绘了一种新的脑-肝回路，在饥饿和肥胖等生理条件下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）在大脑中抑制肝脏交感神经活动并刺激脂质合成。AGRP是发生在饥饿和肥胖的肝脏脂肪变性的必要条件。有趣的是，乙醇刺激小鼠下丘脑中Agrp的表达，而Agrp缺陷小鼠在不改变喂养和体重的情况下对乙醇诱导的肝脂肪变性产生抗性。这项提议的目的是验证乙醇诱导肝脂肪变性的假设，

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.