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A Role of Hypothalamic Dysfunction in Alcoholic Liver Disease

下丘脑功能障碍在酒精性肝病中的作用

基本信息

批准号：
8859014
负责人：
CHRISTOPH BUETTNER
金额：
$ 5.56万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2014-07-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8859014
关键词：
Accounting Adipose tissue Alcohol consumption Alcoholic Liver Diseases Alcoholism Alcohols Amino Acids Animals Autonomic nervous system Brain Cannulas Carbohydrates Chronic Coculture Techniques Complement Conscious Data Defect Dilution Techniques Endoplasmic Reticulum Environment Euglycemic Clamping Genetic Glucose Glucose Clamp Hepatic Hepatocyte Homeostasis Hormones Hypothalamic dysfunction Hypothalamic structure Impairment In Vitro Inflammation Inflammatory Infusion procedures Instruction Insulin Insulin Receptor Insulin Resistance Kupffer Cells Lipids Lipolysis Liver Liver Fibrosis Liver diseases Metabolic Metabolism Modeling Mus Natural Immunity Neurons Neurosecretory Systems Neurotransmitters Organ Oxidative Stress Pathogenesis Pathway interactions Peripheral Play Predisposition Prevention Protein Tyrosine Phosphatase Rattus Regulation Regulatory Pathway Risk Factors Role Signal Pathway Signal Transduction Testing Tracer Transgenic Model Up-Regulation Very low density lipoprotein alcohol effect alcohol research alcohol testing base binge drinking carbohydrate metabolism cell type chronic alcohol ingestion endoplasmic reticulum stress feeding glucose metabolism glucose production glucose tolerance impaired glucose tolerance in vivo inflammatory marker inhibitor/antagonist insulin signaling intrahepatic lipid metabolism mouse model neurotoxic non-alcoholic fatty liver novel prevent restoration small molecule stellate cell

项目摘要

Insulin resistance is an important risk factor for alcoholic liver disease (ALD). Vice versa, heavy alcohol consumption induces insulin resistance that is associated with progression of hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD). Insulin is the key hormone that regulates lipid and glucose metabolism; it is also an important regulator of inflammation. Thus, hepatic insulin action is likely a key player in the pathogenesis of ALD, yet the mechanisms through which impaired insulin action predisposes to ALD remain poorly understood. We and others have previously demonstrated that insulin signaling within the mediobasal hypothalamus (MBH) controls hepatic glucose production (hGP), very low density lipoprotein (VLDL) secretion, white adipose tissue (WAT) lipolysis and innate immunity through the autonomic nervous system. Based on our pilot data that demonstrate that in a rat model for binge drinking, i.e. short term alcohol consumption impairs glucose tolerance and induces insulin resistance that is due to impaired hepatic insulin action. Binge drinking markedly impairs hypothalamic insulin action, defined as the ability of hypothalamic insulin to suppress hGP and adipose tissue lipolysis. Thus, the major hypothesis proposed in this proposal is that some of the metabolic and innate immunity defects induced by alcohol are caused through brain effects disrupting autonomic control of both metabolism and innate immunity. In support ofthis novel paradigm we find that a central cause ofthe impaired hypothalamic insulin action is decreased insulin signaling in the hypothalamus likely due to increased inflammation, ER stress and expression of protein tyrosine phosphatase l b (PTPIb), a negative regulator of insulin signaling. Here we propose to delineate the mechanisms through which chronic alcohol consumption impairs insulin action, disrupts hepatic carbohydrate, amino acid and lipid metabolism and generates a pro-inflammatory environment within the liver that predisposes to ALD.

胰岛素抵抗是酒精性肝病（ALD）的重要危险因素。反之亦然，重度酒精消费会诱导胰岛素抵抗，这与肝纤维化的进展有关非酒精性脂肪肝（NAFLD）。胰岛素是调节脂质和葡萄糖的关键激素代谢;它也是炎症的重要调节剂。因此，肝脏胰岛素作用可能是关键酒精性肝病 (ALD) 发病机制中的一个重要因素，但胰岛素作用受损导致的机制对 ALD 的了解仍知之甚少。我们和其他人之前已经证明，胰岛素信号传导下丘脑内侧基底节 (MBH) 控制肝葡萄糖生成 (hGP)，密度极低脂蛋白（VLDL）分泌、白色脂肪组织（WAT）脂肪分解和先天免疫通过自主神经系统。根据我们的试点数据表明，在酗酒的大鼠模型中，即短期饮酒会损害葡萄糖耐量并诱发胰岛素抵抗，这是由于肝脏胰岛素作用受损。酗酒会明显损害下丘脑胰岛素的作用，定义为下丘脑胰岛素抑制 hGP 和脂肪组织脂解的能力。因此，主要假设该提案提出的是，酒精引起的一些代谢和先天免疫缺陷是由大脑影响破坏新陈代谢和先天免疫的自主控制引起。在为了支持这一新范式，我们发现下丘脑胰岛素作用受损的一个主要原因是下丘脑的胰岛素信号减弱可能是由于炎症增加、内质网应激和蛋白酪氨酸磷酸酶 l b (PTPIb) 的表达，PTPIb 是胰岛素信号传导的负调节因子。在这里我们提议描述长期饮酒损害胰岛素作用的机制，扰乱肝脏碳水化合物、氨基酸和脂质代谢并产生促炎物质肝脏内的环境容易导致 ALD。