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: 10972743
• 负责人: Wei Zhong
• 金额: $ 49.08万
• 依托单位: UNIVERSITY OF KANSAS 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: 2023-06-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10972743
• 关键词: Roles; peroxisomal; dysfunction; alcohol; related

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.

项目总结/摘要 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之一。 然而，ALD的发病机制还不清楚，因此，缺乏 经过验证的疗法。现在新出现的证据表明，胆汁酸异常发挥了致病作用， ALD的发病机制过氧化物酶体是控制细胞代谢过程的动态细胞器，包括 胆汁酸合成虽然早期的研究表明酒精暴露会导致过氧化物酶体损伤， 过氧化物酶体在ALD中的重要性仍然被低估， 过氧化物酶体扰动的机制及其代谢后果，如胆汁酸紊乱， 酒精中毒仍然是初步的。因此，本申请的目的是克服这种知识 通过确定过氧化物酶体功能障碍，随之而来的胆汁酸紊乱和 ALD的发展。我们的初步研究表明，酒精暴露降低了肝脏过氧化物酶体， 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陷（PEX 3敲除）小鼠模型，我们发现 过氧化物酶体对于胆汁酸合成是关键的，PEX 3减少导致 毒性胆汁酸中间体和对酒精的敏感性增加。通过研究分子机制 通过过氧化物酶体功能障碍导致肝损伤，我们发现过氧化物酶体影响线粒体， 和ER动力学，至少部分地，通过胆汁酸中间体。此外，我们还发现了一种强烈的诱导， 脂质运载蛋白2在ALD患者和小鼠以及PEX 3敲除小鼠中的表达。在PEX 3中进一步敲除LCN 2 基因敲除小鼠改善了PEX 3缺陷诱导的肝损伤。这些数据让我们假设酒精 暴露通过靶向诱导过氧化物酶体功能障碍和有毒胆汁酸中间产物的积累 PEX 3，这反过来又促进了ALD的发展。我们提出了三个具体目标来检验假设。 目的1中的研究将确定肝细胞PEX 3减少在使用PEX 3的ALD发病机制中的作用。 基因敲除和酒精中毒小鼠模型;目标2将描述胆汁酸中间体在 目的3探讨肝细胞LCN 2在过氧化物酶体中的作用， ALD中功能障碍引起的肝损伤。从这项研究中获得的知识将使人们更加了解 功能性过氧化物酶体在维持胆汁酸稳态以对抗毒性刺激如酒精中的作用。 该项目预计将通过确定新的分子靶点来预防和/或 ALD及其并发症的治疗