Dynamic human liver proteome atlas reveals functional insights into disease pathways

Deeper understanding of liver pathophysiology would benefit from a comprehensive quantitative proteome resource at cell-type resolution to predict outcome and design therapy. Here, we quantify more than 150,000 sequence-unique peptides aggregated into 10,000 proteins across total liver, the major liver cell types, time-course of primary cell cultures and liver disease states. Bioinformatic analysis reveals that half of hepatocyte protein mass is comprised of enzymes and 23% of mitochondrial proteins, twice the proportion of other liver cell types. Using primary cell cultures, we capture dynamic proteome remodeling from tissue states to cell line states, providing useful information for biological or pharmaceutical research. Our extensive data serves as spectral library to characterize a human cohort of non-alcoholic steatohepatitis and cirrhosis. Dramatic proteome changes in liver tissue include signatures of stellate cell activation resembling liver cirrhosis and providing functional insights. We built a web-based dashboard application for the interactively exploration of our resource at www.liverproteome.org.

若要深入理解肝脏病理生理学，亟需一套具备细胞类型分辨率的全定量蛋白质组学资源，以助力预后预测与治疗方案设计。本研究针对全肝组织、主要肝脏细胞类型、原代细胞培养（primary cell cultures）时序样本以及肝脏疾病状态样本，定量鉴定了超过150,000条序列唯一性肽段，这些肽段可整合为10,000种蛋白质。生物信息学分析显示，肝细胞蛋白质组总质量的一半由酶类构成，其中23%为线粒体蛋白质，该占比是其他肝脏细胞类型的两倍。通过原代细胞培养模型，我们捕捉到了从组织状态到细胞系状态的蛋白质组动态重塑过程，可为生物学与药学研究提供极具价值的参考依据。本研究产生的海量数据可作为谱图库（spectral library），用于表征非酒精性脂肪性肝炎（non-alcoholic steatohepatitis）与肝硬化患者队列的蛋白质组特征。肝组织中发生的显著蛋白质组变化包含肝星状细胞（stellate cell）活化特征，该特征与肝硬化的分子变化模式高度相似，可为相关功能机制研究提供重要见解。我们开发了基于网页的可视化仪表盘应用，供用户交互式探索本研究的数据集资源，访问网址为www.liverproteome.org。