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 酒精性肝病(ALD)一直是全球发病率和死亡率的主要原因之一。 然而，ALD的发病机制还不是很清楚，因此，缺乏 久经考验的疗法。新出现的证据表明，胆汁酸的异常在 ALD的发病机制。过氧化物体是控制细胞代谢过程的动态细胞器，包括 胆汁酸合成。尽管早期的研究表明酒精暴露会导致过氧化物体损伤，但 过氧酶体在ALD中的重要性仍然被低估，留下了关于分子的知识 过氧化体扰动的机制及其代谢后果，如胆汁酸紊乱 酒精中毒仍处于初级阶段。因此，本应用程序的目标是克服这种知识 通过确定过氧酶体功能障碍、随之而来的胆酸紊乱和 ALD的发展。我们的初步研究表明，酒精暴露可降低肝脏过氧化物酶 依赖于关键的过氧化物素PEX3的生物发生在酒精喂养的小鼠和酒精中毒患者中 肝炎。使用一种独特的肝细胞特异性过氧化物酶体缺乏症(PEX3基因敲除)小鼠模型，我们发现 过氧酶体对胆汁酸的合成至关重要，而PEX3的还原会导致全身堆积 有毒的胆汁酸中间体和对酒精的敏感性增加。通过追寻分子机制 通过过氧酶体功能障碍导致肝脏损伤，我们发现过氧化物酶体会影响线粒体 内质网动力学，至少部分是通过胆汁酸中间体。此外，我们发现了一种强烈的诱导性 在ALD患者和小鼠以及PEX3基因敲除小鼠中的Lipocalin 2。PEX3中Lcn2基因的进一步敲除 基因敲除小鼠改善PEX3缺乏所致的肝损伤。这些数据让我们假设酒精 暴露通过靶向导致过氧化体功能障碍和有毒胆汁酸中间体的积聚 PEX3，进而促进ALD的发展。我们提出了三个具体目标来检验这些假说。 Aim 1的研究将确定使用PEX3的肝细胞PEX3减少在ALD发病机制中的作用 基因敲除和酒精中毒小鼠模型；Aim 2将表征胆酸中间体对小鼠的毒性 ALD在肠道-肝脏轴的发展；目标3将探讨肝细胞Lcn2在过氧化物体中的作用 ALD中功能障碍所致的肝损害。从研究中获得的知识将提炼出 维持胆汁酸平衡以对抗酒精等有毒刺激物的功能过氧体。 该项目预计将产生重要影响，为预防和/或 酒精性肝病及其并发症的治疗。