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

酒精相关性肝病（ALD）是世界范围内发病率和死亡率的主要原因。它有一个数组