A brain-liver circuit in regulation of alcoholic liver disease

调节酒精性肝病的脑-肝回路

• 批准号: 8761674
• 负责人: Allison W Xu
• 金额: $ 39.48万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761674
• 关键词: ADORA2B gene; ART protein; Acute; Acyl Coenzyme A; Adenosine; Adenosine A2B Receptor; Alcohol abuse; Alcohol consumption; Alcoholic Fatty Liver; Alcoholic Liver Diseases; Alcohols; American; Attenuated; Biological Assay; Body Weight; Brain; Cessation of life; Chronic; Consumption; Cyclic AMP; Development; Ethanol; Ethanol Metabolism; Etiology; Exhibits; Fasting; Fatty Liver; Genetic; Goals; Heavy Drinking; Hepatic; Human; Hyperphagia; Hypothalamic structure; Leptin; Leptin resistance; Lipids; Liver; Liver diseases; Mediating; Modeling; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurons; Neuropeptides; Norepinephrine; Obesity; Pattern; Peripheral; Phenotype; Physiological; Play; Protein Deficiency; Purinergic P1 Receptors; RNA Interference; Receptor Gene; Receptor Signaling; Regulation; Resistance; Risk Factors; Role; Signal Transduction; Source; Staging; Starvation; Sympathectomy; Testing; Therapeutic; Triglycerides; United States; United States Food and Drug Administration; Wild Type Mouse; alcohol effect; binge drinking; chronic alcohol ingestion; chronic liver disease; diacylglycerol O-acyltransferase; falls; feeding; gain of function; in vivo; inhibitor/antagonist; lipid metabolism; liver injury; loss of function; non-alcoholic fatty liver; novel; novel strategies; phrases; prevent; public health relevance; research study; response

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.

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200万美国人患有由酒精引起的肝病。尽管肝脂肪变性是重度饮酒者中普遍存在的表型，但其发生的机制尚不清楚。目前认为酒精直接作用于肝脏，改变脂质代谢，导致肝脂肪变性的发生。我们的实验室最近描绘了一种新型脑肝回路，可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鼠相关蛋白（AGRP）在大脑中发挥作用，抑制肝交感神经活动并刺激脂质合成。 AGRP 是饥饿和肥胖时发生的肝脂肪变性的发生所必需的。有趣的是，施用乙醇会刺激小鼠下丘脑中的 Agrp 表达，并且 AGRP 缺陷的小鼠能够抵抗乙醇诱导的肝脂肪变性，而不改变摄食和体重。该提案的目的是检验乙醇诱导肝脂肪变性的假设， 至少部分是通过刺激下丘脑 Agrp 表达，导致肝交感神经活动的改变和肝脂肪变性的发展。将确定酒精对 Agrp 表达和肝脂肪变性影响的信号机制。我们将进一步研究调节肝交感神经活性在乙醇诱导的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 减轻长期酗酒引起的肝损伤。总而言之，该提案中概述的实验将确定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。