Molecular alterations associated with pathophysiology in liver-specific ZO-1 and ZO-2 knockout mice.

IF 2 4区 生物学 Q4 CELL BIOLOGY
Cell structure and function Pub Date : 2024-10-26 Epub Date: 2024-09-26 DOI:10.1247/csf.24046
Masahiko Itoh, Kenji Watanabe, Yoichi Mizukami, Hiroyuki Sugimoto
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引用次数: 0

Abstract

The liver is a complex organ with a highly organized structure in which tight junctions (TJs) play an important role in maintaining their function by regulating barrier properties and cellular polarity. Dysfunction of TJs is associated with liver diseases, including progressive familial intrahepatic cholestasis (PFIC). In this study, we investigated the molecular alterations in a liver-specific ZO-1 and ZO-2 double-knockout (DKO) mouse model, which exhibits features resembling those of PFIC4 patients with mutations in the ZO-2 gene. RNA-seq analysis revealed the upregulation of genes involved in the oxidative stress response, xenobiotic metabolism, and cholesterol metabolism in DKO livers. Conversely, the expression of genes regulated by HNF4α was lower in DKO livers than in the wild-type controls. Furthermore, age-associated analysis elucidated the timing and progression of these pathway changes as well as alterations in molecules related to TJs and apical polarity. Our research uncovered previously unknown implications of ZO-1 and ZO-2 in liver physiology and provides new insights into the molecular pathogenesis of PFIC4 and other tight junction-related liver diseases. These findings contribute to a better understanding of the complex mechanisms underlying liver function and dysfunction and may lead to the development of novel therapeutic strategies for liver diseases associated with tight junction impairment.Key words: tight junctions, ZO-1/ZO-2 knockout mouse, liver, transcriptome analysis, molecular pathological progression.

与肝特异性 ZO-1 和 ZO-2 基因敲除小鼠病理生理学相关的分子变化
肝脏是一个具有高度组织结构的复杂器官,其中紧密连接(TJ)通过调节屏障特性和细胞极性在维持其功能方面发挥着重要作用。TJs 功能障碍与肝脏疾病有关,包括进行性家族性肝内胆汁淤积症(PFIC)。在本研究中,我们研究了肝脏特异性 ZO-1 和 ZO-2 双基因敲除(DKO)小鼠模型的分子变化,该模型表现出与 ZO-2 基因突变的 PFIC4 患者相似的特征。RNA-seq分析显示,DKO肝脏中参与氧化应激反应、异种生物代谢和胆固醇代谢的基因上调。相反,DKO肝脏中受HNF4α调控的基因表达低于野生型对照组。此外,与年龄相关的分析阐明了这些通路变化的时间和进展,以及与TJ和顶端极性相关的分子的改变。我们的研究揭示了ZO-1和ZO-2在肝脏生理学中之前未知的意义,并为PFIC4和其他与紧密连接相关的肝脏疾病的分子发病机制提供了新的见解。这些发现有助于更好地理解肝脏功能和功能障碍的复杂机制,并可能为与紧密连接损伤相关的肝脏疾病开发新的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell structure and function
Cell structure and function 生物-细胞生物学
CiteScore
2.50
自引率
0.00%
发文量
6
审稿时长
>12 weeks
期刊介绍: Cell Structure and Function is a fully peer-reviewed, fully Open Access journal. As the official English-language journal of the Japan Society for Cell Biology, it is published continuously online and biannually in print. Cell Structure and Function publishes important, original contributions in all areas of molecular and cell biology. The journal welcomes the submission of manuscripts on research areas such as the cell nucleus, chromosomes, and gene expression; the cytoskeleton and cell motility; cell adhesion and the extracellular matrix; cell growth, differentiation and death; signal transduction; the protein life cycle; membrane traffic; and organelles.
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