Role of Adipose in Ethanol-Induced Tissue Injury

脂肪在乙醇引起的组织损伤中的作用

基本信息

批准号：
9521872
负责人：
LAURA E. NAGY
金额：
$ 41.51万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-04-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9521872
关键词：
Adipocytes Adipose tissue Affect Alcohol abuse Alcohol consumption Alcoholic Liver Diseases American Antibodies Apoptosis Appetitive Behavior C5a anaphylatoxin receptor Cell surface Chronic Classical Complement Pathway Complement 1q Complement 3a Complement 5a Complement Activation Complement Inactivators Data Development Ethanol Ethanol Metabolism Generations Glucose Glucose Intolerance Goals Grant HIF1A gene Hepatic Homeostasis Hypoxia Immunoglobulin M Individual Inflammation Inflammatory Response Injury Instruction Insulin Resistance Kidney Knock-out Light Lipids Liver Liver diseases Mediating Metabolic Metabolic Diseases Metabolic syndrome Molecular Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus Organ Pathway interactions Proteomics Rattus Regulation Research Research Project Grants Risk Role Skeletal Muscle Testing Tissues adipokines alcohol effect alcohol exposure chronic alcohol ingestion complement pathway epidemiology study feeding insulin sensitivity knock-down macrophage mortality novel therapeutics oxidized lipid prevent recruit response

项目摘要

Alcohol abuse is a leading cause of morbidity and mortality worldwide and recent data indicate that alcoholic liver disease affects over 10 million Americans. Epidemiological studies suggest that alcohol consumption also modulates the risk for the development of type 2 diabetes, the most common metabolic disease among older North Americans, with light alcohol consumption decreasing risk and chronic heavy alcohol consumption increasing risk in a J-shaped curve. Chronic, heavy ethanol exposure results in the development of glucose intolerance and insulin resistance. Since insulin resistance is commonly associated with the progression of liver disease in individuals with metabolic syndrome, as well as the development of type 2 diabetes, we hypothesize that ethanol-induced insulin resistance also contributes to the progression of alcoholic liver disease. In the past granting period, we have made significant progress in understanding the molecular and cellular mechanisms by which chronic, heavy ethanol feeding results in the development of insulin resistance, both in relation to glucose and lipid homeostasis. We have identified adipose tissue as a specific target of ethanol action. While the role of adipose tissue in the regulation of energy stores has long been appreciated, there is a growing understanding for the critical role of adipose tissue in regulating metabolic homeostasis, including the ability to modulate insulin sensitivity in skeletal muscle and liver, contribute to the regulation of inflammatory responses, as well as regulating appetitive behaviors. Given these essential roles for adipose tissue, the long-term goals of this research project are to investigate the mechanisms by which ethanol disrupts the metabolic and regulatory activity of adipose tissue and.determine the impact of these chronic ethanol-induced changes in adipose tissue in mediating the pathophysiological effects of chronic ethanol. During the extension of this research plan, we propose to investigate the hypothesis that changes in the metabolic and regulatory activity of adipose tissue in response to chronic ethanol consumption are important contributors to spreading of tissue injury between organs, particularly to the liver and kidney. We will investigate the following specific aims: Specific Aim 1: Determine the molecular and cellular mechanisms for activation of complement in adipose tissue after chronic ethanol exposure; Specific Aim 2: Determine if blockade of the Clq pathway and complement activation can prevent or reverse adipose tissue inflammation and insulin resistance after chronic ethanol; Specific Aim 3: Understand the broader impact on the ethanol on the adipocyte secretome and the influence of the adipose secretome in the spread of tissue injury after chronic ethanol feeding. Understanding the mechanisms by which chronic ethanol disrupts the metabolic and regulatory activity of adipose tissue, and the impact of these changes on hepatic function, will likely lead to the development of novel therapeutic strategies to prevent and/or reverse alcoholic liver disease. RELEVANCE (See instructions): Alcohol abuse is a leading cause of morbidity and mortality worldwide and recent data indicate that alcoholic liver disease affects over 10 million Americans. The long-term goals of this research project are to investigate the mechanisms by which ethanol disrupts the metabolic activity of adipose tissue and determine the impact of these chronic ethanol-induced changes in adipose tissue in the development of alcoholic liver disease.

酗酒是全球发病率和死亡率的主要原因，最近的数据表明酒精性肝脏疾病影响超过1000万美国人。流行病学研究表明，饮酒也调节2型糖尿病的发展风险，这是北方旧北部最常见的代谢疾病美国人，饮酒量降低风险，慢性大量饮酒量增加了风险 J形曲线。慢性乙醇暴露导致葡萄糖不耐症和胰岛素的发展反抗。由于胰岛素抵抗通常与患有肝病的进展有关代谢综合征以及2型糖尿病的发展，我们假设乙醇诱导的胰岛素抗药性也有助于酒精性肝病的进展。在过去的授予期间，我们做出了在理解慢性，重型乙醇进食的分子和细胞机制方面的重大进展导致胰岛素抵抗的发展，包括葡萄糖和脂质稳态。我们已经确定了脂肪组织作为乙醇作用的特定靶标。而脂肪组织在能量调节中的作用长期以来一直对商店表示赞赏，对脂肪组织在调节代谢稳态，包括调节骨骼肌和肝脏中胰岛素敏感性的能力，有助于调节炎症反应以及调节食用行为。鉴于这些脂肪组织的重要作用，该研究项目的长期目标是研究机制乙醇破坏脂肪组织的代谢和调节活性，并确定的影响这些慢性乙醇引起的脂肪组织的变化在介导慢性的病理生理作用时乙醇。在扩展本研究计划期间，我们提出了以下假设。脂肪组织对慢性乙醇消耗的代谢和调节活性很重要器官之间，特别是肝脏和肾脏之间组织损伤的贡献者。我们将调查以下特定目的：特定目标1：确定激活的分子和细胞机制慢性乙醇暴露后的脂肪组织补体；特定目标2：确定CLQ的阻滞途径和补体激活可以预防或反向脂肪组织炎症和胰岛素抵抗慢性乙醇之后；特定目的3：了解对乙醇对脂肪细胞分泌的更广泛影响以及脂肪分泌组对慢性乙醇进食后组织损伤扩散的影响。了解慢性乙醇破坏脂肪的代谢和调节活性的机制组织以及这些变化对肝功能的影响可能会导致新颖的发展预防和/或反向酒精性肝病的治疗策略。相关性（请参阅说明）：酒精滥用是全球发病率和死亡率的主要原因，最近的数据表明酒精肝病影响超过1000万美国人。该研究项目的长期目标是研究乙醇破坏脂肪组织的代谢活性的机制并确定这些慢性乙醇诱导的脂肪组织变化在酒精肝发育中的影响疾病。