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肝纤维化肝毒性和胆汁淤积模型中特定区室蛋白质组学景观的动态变化

Dynamics of compartment-specific proteomic landscapes of hepatotoxic and cholestatic models of liver fibrosis.

作者信息

Jirouskova Marketa, Harant Karel, Cejnar Pavel, Ojha Srikant, Korelova Katerina, Sarnova Lenka, Sticova Eva, Mayr Christoph H, Schiller Herbert B, Gregor Martin

机构信息

Laboratory of Integrative Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.

Laboratory of Mass Spectrometry, BIOCEV, Faculty of Science, Charles University, Prague, Czech Republic.

出版信息

Elife. 2025 Apr 8;13:RP98023. doi: 10.7554/eLife.98023.

DOI:10.7554/eLife.98023
PMID:40197391
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11978302/
Abstract

Accumulation of extracellular matrix (ECM) in liver fibrosis is associated with changes in protein abundance and composition depending upon etiology of the underlying liver disease. Current efforts to unravel etiology-specific mechanisms and pharmacological targets rely on several models of experimental fibrosis. Here, we characterize and compare dynamics of hepatic proteome remodeling during fibrosis development and spontaneous healing in experimental mouse models of hepatotoxic (carbon tetrachloride [CCl] intoxication) and cholestatic (3,5-diethoxycarbonyl-1,4-dihydrocollidine [DDC] feeding) injury. Using detergent-based tissue extraction and mass spectrometry, we identified compartment-specific changes in the liver proteome with detailed attention to ECM composition and changes in protein solubility. Our analysis revealed distinct time-resolved CCl and DDC signatures, with identified signaling pathways suggesting limited healing and a potential for carcinogenesis associated with cholestasis. Correlation of protein abundance profiles with fibrous deposits revealed extracellular chaperone clusterin with implicated role in fibrosis resolution. Dynamics of clusterin expression was validated in the context of human liver fibrosis. Atomic force microscopy of fibrotic livers complemented proteomics with profiles of disease-associated changes in local liver tissue mechanics. This study determined compartment-specific proteomic landscapes of liver fibrosis and delineated etiology-specific ECM components, providing thus a foundation for future antifibrotic therapies.

摘要

肝纤维化过程中细胞外基质（ECM）的积累与蛋白质丰度和组成的变化有关，具体取决于潜在肝脏疾病的病因。目前，为揭示病因特异性机制和药理靶点所做的努力依赖于几种实验性纤维化模型。在此，我们在肝毒性（四氯化碳 [CCl] 中毒）和胆汁淤积性（喂食3,5-二乙氧基羰基-1,4-二氢可力丁 [DDC]）损伤的实验小鼠模型中，对纤维化发展和自发愈合过程中肝脏蛋白质组重塑的动态变化进行了表征和比较。使用基于去污剂的组织提取和质谱分析，我们确定了肝脏蛋白质组中特定区室的变化，并详细关注了ECM组成和蛋白质溶解度的变化。我们的分析揭示了不同的时间分辨CCl和DDC特征，所确定的信号通路表明胆汁淤积相关的愈合有限且有致癌潜力。蛋白质丰度谱与纤维沉积物的相关性揭示了细胞外伴侣蛋白簇集素在纤维化消退中具有潜在作用。在人类肝纤维化背景下验证了簇集素表达的动态变化。纤维化肝脏的原子力显微镜检查通过局部肝组织力学中与疾病相关变化的概况补充了蛋白质组学。这项研究确定了肝纤维化的特定区室蛋白质组格局，并描绘了病因特异性的ECM成分，从而为未来的抗纤维化治疗奠定了基础。

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