Role of Adipose in Ethanol-Induced Tissue Injury

脂肪在乙醇引起的组织损伤中的作用

• 批准号: 8602009
• 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
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8602009
• 关键词: Adipocytes; Adipose tissue; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Liver Diseases; American; Appetitive Behavior; Chronic; Complement Activation; Data; Development; Epidemiologic Studies; Ethanol; Glucose; Glucose Intolerance; Goals; Grant; Hepatic; Homeostasis; Individual; Inflammation; Inflammatory Response; Injury; Instruction; Insulin Resistance; Kidney; Lead; Light; Lipids; Liver; Liver diseases; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Molecular; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pathway interactions; Regulation; Research; Research Project Grants; Risk; Role; Shapes; Skeletal Muscle; Tissues; alcohol exposure; chronic alcohol ingestion; feeding; insulin sensitivity; mortality; novel therapeutics; prevent; response

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.

酒精滥用是全世界发病和死亡的主要原因，最近的数据表明酒精肝 该疾病影响了超过 1000 万美国人。流行病学研究表明饮酒也会 调节 2 型糖尿病的发展风险，2 型糖尿病是北方老年人中最常见的代谢疾病 美国人，少量饮酒会降低风险，而长期大量饮酒会增加风险 J 形曲线。长期大量接触乙醇会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以下疾病的个体的肝病进展有关 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 抵抗力也会导致酒精性肝病的进展。在过去的拨款期间，我们已经做出了 在理解长期大量乙醇喂养的分子和细胞机制方面取得了重大进展 导致胰岛素抵抗的发展，这与葡萄糖和脂质稳态有关。我们已经确定 脂肪组织作为乙醇作用的特定目标。而脂肪组织在能量调节中的作用 脂肪组织长期以来一直受到重视，人们越来越了解脂肪组织的关键作用 调节代谢稳态，包括调节骨骼肌和肝脏胰岛素敏感性的能力， 有助于调节炎症反应以及调节食欲行为。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其机制 乙醇通过这种方式破坏脂肪组织的代谢和调节活性，并确定其影响 这些慢性乙醇诱导的脂肪组织变化在介导慢性酒精的病理生理作用中 乙醇。在本研究计划的扩展期间，我们建议调查以下假设： 脂肪组织对长期乙醇消耗的代谢和调节活动很重要 导致器官间组织损伤扩散，特别是肝脏和肾脏。我们将调查 具体目标如下： 具体目标 1：确定激活的分子和细胞机制 慢性乙醇暴露后脂肪组织中的补体；具体目标 2：确定 Clq 是否被封锁 途径和补体激活可以预防或逆转脂肪组织炎症和胰岛素抵抗 长期饮酒后；具体目标 3：了解乙醇对脂肪细胞分泌组的更广泛影响 以及脂肪分泌组对慢性乙醇喂养后组织损伤扩散的影响。 了解长期乙醇破坏脂肪代谢和调节活动的机制 组织，以及这些变化对肝功能的影响，可能会导致新的开发 预防和/或逆转酒精性肝病的治疗策略。 相关性（参见说明）： 酒精滥用是全世界发病和死亡的主要原因，最近的数据表明，酒精滥用 肝病影响着超过 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代谢活动的机制并确定 这些慢性乙醇引起的脂肪组织变化对酒精肝发展的影响 疾病。