Development and Progression of Alcohol-Associated Liver Disease: Effect of Aging

酒精相关肝病的发生和进展：衰老的影响

• 批准号: 10526259
• 负责人: Kusum K. Kharbanda
• 金额: $ 24.18万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-28 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10526259
• 关键词: Adipose tissue; Advanced Development; Age; Aging; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Animals; Bacterial Translocation; Biological; Body Composition; Cell physiology; Chronic; Circulation; Cirrhosis; Clinical; Defect; Development; Diet; Disease Outcome; Disease Progression; Dose; Eating; Elderly; Endothelial Cells; Endotoxins; Energy Metabolism; Ethanol; Exhibits; Experimental Designs; Exposure to; Extrahepatic; Functional disorder; Gastrointestinal tract structure; Gender; Genetic; Heavy Drinking; Hepatic; Hepatic Stellate Cell; Hepatocyte; Hormones; Impairment; Inflammation Mediators; Insulin; Investigation; Kupffer Cells; Life Style; Lipolysis; Liver; Liver Circulation; Liver diseases; Metabolism; Methods; Morbidity - disease rate; Motor Activity; Mucous Membrane; Nebraska; Nonesterified Fatty Acids; Organ; Pathogenesis; Pathogenicity; Pathology; Patients; Pattern; Persons; Physiological; Play; Primary carcinoma of the liver cells; Recording of previous events; Research; Risk Factors; Rodent; Role; Sampling; Severities; Severity of illness; Steatohepatitis; Structure; Testing; Virus Diseases; Water consumption; adipokines; adiponectin; age effect; aging population; alcohol exposure; alcohol misuse; alcohol response; biobank; body system; cell type; chronic alcohol ingestion; chronic liver disease; diet and exercise; disease phenotype; drinking; glucose uptake; gut microbiota; insight; intestinal barrier; juvenile animal; liver injury; mortality; older patient; simple steatosis; trend

Alcohol-associated liver disease (ALD) is a major cause of morbidity and mortality worldwide. It has an array of liver pathologies that ranges from simple fatty liver to more severe forms of liver injury such as steatohepatitis, cirrhosis, and hepatocellular carcinoma. Many extrahepatic factors including genetics, gender, lifestyle (diet and exercise) and exposures to viral infections determine the disease phenotype and outcome. Equally important in ALD pathogenesis and progression is the associated dysfunction of other organs. It is now well- documented that the alcohol-induced changes in the gut microbiota and disruption of the intestinal barrier integrity resulting in the increased translocation of bacterial-derived byproducts into the portal-hepatic circulation plays a crucial pathogenic role in ALD progression. In adipose tissue, chronic ethanol consumption enhances lipolysis, impairs insulin-activated glucose uptake, reduces secretion of protective adipokines, and enhances release of pro-inflammatory mediators, all of which contribute to ALD pathogenesis. Aging is a predominant risk factor for the development of advanced chronic liver diseases. Emerging evidence indicates that advanced age is associated with alterations to the hepatic structure and impairment of cellular functions. There are also aging-related detrimental changes in adipose tissue as well as in the composition/ stability of gut microbiota and barrier integrity. Many of these aging-related alterations in the elderly resemble ethanol-induced defects in the liver, adipose and gut organ systems. Based on these considerations we hypothesize that aging-related structural and functional changes in the gastrointestinal tract, adipose and liver in older subjects promote a faster progression of ALD than in younger subjects. Here, we propose to conduct an in-depth study to examine the effect of aging on ALD severity. This study is warranted given the upward trend for heavy drinking among the elderly and the global expansion in the aging population which is predicted to double to over 1.5 billion persons by 2050. To test our hypothesis, we propose the following Specific Aims: Specific Aim 1: Examine the aging-related structural and functional changes in the gastrointestinal tract, adipose and liver of ethanol-fed rodents Specific Aim 2: Gain mechanistic insight into how ethanol administration to older and younger animals for the same duration generates more severe liver injury in older subjects Specific Aim 3: Identify and analyze aging-related changes in patients with alcohol-associated liver disease in relation to the severity of liver disease

酒精相关肝病（ALD）是全球发病率和死亡率的主要原因。它有一系列 肝脏病理，从简单脂肪肝脏到更严重的肝损伤，例如脂肪性肝炎， 肝硬化和肝细胞癌。许多肝外因素，包括遗传学，性别，生活方式（饮食 运动）和暴露于病毒感染决定了疾病的表型和结果。同样 在ALD发病机理和进展中重要的是其他器官的相关功能障碍。现在很好 记录了酒精引起的肠道菌群的变化和肠屏障的破坏 完整性导致细菌衍生的副产物易位的易位增加 循环在ALD进展中起着至关重要的致病作用。在脂肪组织中，慢性乙醇消耗 增强脂解，损害胰岛素激活的葡萄糖摄取，减少保护性脂肪因子的分泌，并 增强促炎性介体的释放，所有这些都导致了ALD发病机理。 衰老是发展晚期慢性肝病的主要风险因素。新兴证据 表明高龄与肝结构的改变和细胞损伤有关 功能。脂肪组织以及组成/ 肠道菌群和屏障完整性的稳定性。这些与老年人相关的这些变化中的许多类似 乙醇诱导的肝脏，脂肪和肠道器官系统中的缺陷。 根据这些考虑，我们假设与衰老相关的结构和功能变化 老年受试者中的胃肠道，脂肪和肝脏促进了ALD的更快进展 年轻的受试者。在这里，我们建议进行一项深入研究以检查衰老对ALD的影响 严重程度。鉴于老年人和全球大量饮酒的上升趋势是有必要的 到2050年，老龄化人口的扩张预计将增加到15亿人。 为了检验我们的假设，我们提出以下特定目的： 特定目标1：检查胃肠道中与衰老相关的结构和功能变化， 乙醇喂养啮齿动物的脂肪和肝脏 特定目的2：获得机械洞察乙醇如何用于年龄较大的动物的乙醇 相同的持续时间在较老的受试者中会产生更严重的肝脏损伤 特定目的3：识别和分析与酒精相关肝病患者的衰老相关变化 关于肝病的严重程度