A brain-liver circuit in regulation of alcoholic liver disease

描述(申请人提供)：肝病是美国疾病和死亡的主要原因之一。过度饮酒是肝脏损伤的主要风险因素，超过200万美国人患有酒精引起的肝病。虽然肝脏脂肪变性是重度饮酒者中的一种流行表型，但其发生机制尚不清楚。目前认为酒精直接作用于肝脏，改变脂肪代谢，导致肝脏脂肪变性。我们的实验室最近描绘了一个新的脑-肝脏回路，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，下丘脑神经肽刺激性相关蛋白(AGRP)在大脑中起作用，抑制肝脏交感神经活动，刺激脂质合成。在饥饿和肥胖引起的肝脏脂肪变性的发展过程中，AgRP是必需的。有趣的是，乙醇能刺激小鼠下丘脑中AgRP的表达，AGRP缺陷的小鼠在不改变摄食和体重的情况下，可以抵抗乙醇诱导的肝脏脂肪变性。这项提议的目的是检验乙醇导致肝脏脂肪变性的假设， 至少部分通过刺激下丘脑AgRP表达，导致肝脏交感神经活性改变，发展为肝脏脂肪变性。酒精对AgRP表达和肝脏脂肪变性影响的信号机制将被确定。我们将进一步探讨调节肝脏交感神经活性在酒精性肝脂肪变性中的重要性。最后，我们将评估RNA干扰对AgRP的治疗潜力。 减轻慢性酗酒所致的肝损伤。综上所述，这项提案中概述的实验将定义一种新的机制，该机制是酒精诱导的肝脏脂肪变性的基础，并将探索一种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.