A Cytological Atlas of Human Liver Proteome from PROTEOME SKY -LIVER Hu 2.0, A Publicly Available Database

Liver plays a unique role as a metabolic center of the body, and also performs other important functions such as detoxification and immune response. The regulatory networks are formed between hepatocytes and non-parenchymal liver cells in human liver to maintain liver homeostasis. But an in-depth knowledge of the constituent proteins in different human liver cell types is still lacking. Here, we determine the healthy human liver proteome by measuring four major cell types that build classical liver lobule, hepatocytes (HCs), hepatic stellate cells (HSCs), Kupffer cells (KCs), and liver sinusoidal endothelial cells (LSECs) by high-resolution mass spectrometry-based proteomics. Overall, we quantify a total of 8,354 proteins for four cell types and over 6,000 proteins for each cell type. Analysis of this dataset and regulatory pathway reveals the cellular labor division in human liver follows the pattern that parenchymal cells make the main components of pathways, but non-parenchymal cells trigger the pathways. The cells in human liver show some novel molecular features, HCs maintain KC and LSEC homeostasis by producing cholesterol and ketone body; HSCs participate xenobiotics metabolism as an agent deliver; KCs and LSECs mediate immune response through MHC class II-TLRs and MHC class I-TGFβ cascade, respectively; KCs play a central role in diurnal rhythms regulation through sensing diurnal IGF and temperature flux . Together, this work expands our understandings of liver physiology on the basis of cell type resolved proteomics of healthy human liver and provides a useful resource for future analyses of normal and diseased livers. Funding: This work was partially supported by National Key R&D Program of China (Nos.2018YFA0507502, 2020YFE0202200), National Natural Science Foundation of China (Nos. 82090051, 81770581 and 81570526), and Open Project Program of the State Key Laboratory of Proteomics (Academy of Military Medical Sciences, SKLP-K201801, SKLP-K201901, SKLP-O201902 and SKLP-O202001) Declaration of Interest: There is no competing interest in this study. Ethical Approval: This study was approved by the Ethics Committee of The third medical 407 center of Chinese PLA general hospital (Beijing, China).