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.

项目摘要 /摘要 与酒精有关的肝病（ALD）一直是全球发病率和死亡率的主要原因之一。 但是，ALD中的致病机制尚不清楚，因此，没有 经过验证的疗法。现在有新兴的证据表明，胆汁酸异常在 ALD的发病机理。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。尽管早期研究表明酒精暴露时过氧化物酶体损害，但 过氧化物酶体在ALD中的重要性仍被低估，留下了有关分子的知识 过氧化物酶体扰动的机制及其代谢后果，例如胆汁酸障碍，对 酒精中毒仍然是基本的。因此，本应用的目的是克服这一知识 通过确定过氧化物酶体功能障碍，随之而来的胆汁酸障碍和 ALD的发展。我们的初步研究表明，酒精暴露会降低肝过氧化物酶体 饮酒小鼠和酒精性患者的生物发生取决于关键的过氧蛋白PEX3 肝炎。使用独特的肝细胞特异性过氧化物酶体缺乏（PEX3敲除）的鼠标模型，我们发现 过氧化物酶体对于胆汁酸的合成至关重要，而PEX3还原会导致全身积累 有毒的胆汁酸中间体并增加对酒精的敏感性。通过追求分子机制 过氧化物酶体功能障碍会导致肝损伤，我们发现过氧化物酶体会影响线粒体 至少部分通过胆汁酸中间体进行了ER动力学。此外，我们发现 ALD患者和小鼠以及PEX3基因敲除小鼠中的Lipocalin 2。 PEX3中的LCN2进一步淘汰 敲除小鼠可以改善PEX3缺乏引起的肝损伤。这些数据导致我们假设酒精 暴露会导致过氧化物酶体功能障碍和通过靶向毒性胆汁酸中间体的积累 PEX3反过来促进了ALD的发展。我们提出了三个特定的目的来检验假设。 AIM 1中的研究将确定使用PEX3的肝细胞PEX3降低在ALD发病机理中的作用 敲除和酒精醉酒小鼠模型； AIM 2将表征胆汁酸中间体的毒性 肠轴轴的ALD的发展； AIM 3将探索肝细胞LCN2在过氧化物酶体中的作用 功能障碍引起的ALD肝损伤。从研究中获得的知识将完善 在维持胆汁酸稳态以对抗有毒刺激（例如酒精）时，功能过氧化物组。 预计该项目将通过为预防和/或 治疗ALD及其并发症。