A brain-liver circuit in regulation of alcoholic liver disease

调节酒精性肝病的脑-肝回路

基本信息

批准号：
9302619
负责人：
Allison W Xu
金额：
$ 40.08万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/9302619
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 Impairment Leptin Leptin resistance Lipids Liver Liver diseases Mediating Modeling Mus National Institute on Alcohol Abuse and Alcoholism Neurons Neuropeptides Norepinephrine Obesity Pattern Peripheral Pharmacology Phenotype Physiological Play Protein Deficiency Purinergic P1 Receptors RNA Interference Receptor Gene Receptor Signaling Regulation Resistance Risk Factors Role Signal Transduction Source 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 experimental study 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 receptor response

项目摘要

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。饮酒过量是肝脏损害的主要危险因素，超过200万美国人患有饮酒引起的肝病。尽管肝脂肪变性是浓饮酒者的普遍表型，但其发育开发的机制尚不清楚。目前，人们认为酒精直接作用于肝脏，以改变脂质代谢，从而导致肝脂肪变性的发展。我们的实验室最近在生理条件（如饥饿和肥胖症）下，在调节非酒精脂肪肝的调节中描述了一种新型的脑肝电路。我们表明，下丘脑神经肽Agouti相关蛋白（AGRP）在大脑中起作用以抑制肝交感神经活性并刺激脂质合成。 AGRP是饥饿和肥胖症中发生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，而AGRP缺陷小鼠对乙醇诱导的肝脂肪变性的发育具有抵抗力，而不会改变进食和体重的改变。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，从而改变了肝交感神经活性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传导机制。我们将进一步研究调节乙醇引起的肝脂肪变性中肝交感神经活性的重要性。最后，我们将评估RNA与AGRP的治疗潜力慢性加饮酒诱发的肝损伤。综上所述，该提案中概述的实验将定义一种新的机制，该机制是乙醇诱导的肝脂肪变性病因的基础，并将探索一种治疗酒精性肝病的新策略。