Roles of peroxisomal dysfunction in alcohol-related liver disease

过氧化物酶体功能障碍在酒精相关性肝病中的作用

• 批准号: 10659535
• 负责人: Wei Zhong
• 金额: --
• 依托单位: UNIVERSITY OF NORTH CAROLINA GREENSBORO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2023-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10659535
• 关键词: Acetaldehyde; Address; Affect; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Intoxication; Alcoholic Liver Diseases; Alcohols; Bile Acid Biosynthesis Pathway; Bile Acids; Biogenesis; Cell Culture Techniques; Cellular Metabolic Process; Chronic; Circulation; Data; Development; Disease; Disease Progression; Ethanol Metabolism; Exposure to; FDA approved; Functional disorder; Genetic; Goals; Hepatic; Hepatocellular Damage; Hepatocyte; Homeostasis; In Vitro; Inflammation; Intestines; Knock-out; Knockout Mice; Knowledge; LCN2 gene; Link; Liver; Macrophage; Mediating; Metabolic; Metabolic Diseases; Mitochondria; Molecular; Molecular Target; Morbidity - disease rate; Mus; Organ; Organelles; Pathogenesis; Patients; Play; Predisposition; Prevention; Reporting; Research; Role; Signal Transduction; Stimulus; Testing; Therapeutic Intervention; Toxic effect; Virus; alcohol abuse therapy; alcohol exposure; cell type; combat; cytotoxicity; dysbiosis; effective therapy; gain of function; gut-liver axis; hepatoprotective; insight; liver inflammation; liver injury; loss of function; microbial; molecular targeted therapies; mortality; mouse model; novel; overexpression; peroxisome; toxicant; tumorigenesis

PROJECT SUMMARY / ABSTRACT Alcohol-related liver disease (ALD) has been among the leading causes of morbidity and mortality worldwide. However, the pathogenetic mechanisms in ALD are not well understood and, as such, there is an absence of proven therapies. Emerging evidence now suggests that bile acid abnormalities play a causative role in the pathogenesis of ALD. Peroxisomes are dynamic organelles controlling cellular metabolic processes, including bile acid synthesis. Although early studies have implicated peroxisomal damage upon alcohol exposure, the significance of peroxisomes in ALD is still being underestimated, leaving knowledge about the molecular mechanisms of peroxisomal perturbation and its metabolic consequence, such as bile acid disorder, upon alcohol intoxication remain rudimentary. Thus, the objective of this application is to overcome this knowledge gap by determining the link between peroxisomal dysfunction, the consequent bile acid disorder, and the development of ALD. Our preliminary studies suggest that alcohol exposure decreases hepatic peroxisomal biogenesis in a manner dependent on a key peroxin, PEX3, in both alcohol-fed mice and patients with alcoholic hepatitis. Using a unique mouse model of hepatocyte-specific peroxisome deficiency (PEX3 knockout), we found that peroxisomes are critical for bile acid synthesis and that PEX3 reduction causes systemic accumulation of toxic bile acid intermediates and increased susceptibility to alcohol. By pursuing the molecular mechanism through which peroxisomal dysfunction causes liver damage, we found that peroxisome affects mitochondrial and ER dynamics, at least partially, through bile acid intermediates. Moreover, we found a strong induction of lipocalin 2 in ALD patients and mice as well as in PEX3 knockout mice. Further knockout of LCN2 in PEX3 knockout mice ameliorates PEX3 deficiency-induced liver injury. These data led us to hypothesize that alcohol exposure induces peroxisomal dysfunction and the accumulation of toxic bile acid intermediates via targeting PEX3, which in turn, promotes the development of ALD. We propose three Specific Aims to test the hypotheses. Studies in Aim 1 will determine the role of hepatocyte PEX3 reduction in the pathogenesis of ALD using PEX3 knockout and alcohol intoxication mouse models; Aim 2 will characterize the toxicity of bile acid intermediates in the development of ALD at the gut-liver axis; Aim 3 will explore the role of hepatocyte LCN2 in peroxisomal dysfunction-induced liver damage in ALD. Knowledge obtained from the study will refine the importance of functional peroxisomes in maintaining bile acid homeostasis to combat against toxic stimuli, such as alcohol. The project is expected to have an important impact by defining new molecular targets for the prevention and/or treatment of ALD and its complications.

项目摘要/摘要