Signature of Gene Expression Profile of Liver Sinusoidal Endothelial Cells in Nonalcoholic Steatohepatitis

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2022 Oct 10

PMID 36211451

Authors

Yang Wang

Yifan Zhang

Yimin Li

Yun Liu

Yulan Liu

Affiliations

Soon will be listed here.

Abstract

There has been emerging evidence that liver sinusoidal endothelial cells (LSECs) play an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH). This study aims to figure out the signature of the gene expression profile of LSECs in NASH and to explore potential biomarkers related to damaged LSECs in NASH. Animal experiments were performed to demonstrate the significant structural damage of LSECs in the NASH model. To further understand the functional changes of these damaged LSECs in NASH, we used the public GEO database that contained microarray data for the gene expression of LSECs in NASH and normal mouse liver. Differentially expressed genes (DEGs) were analyzed, and further Gene Ontology (GO) enrichment analysis was performed to understand the functional changes. The hub genes were then identified and validated external GEO databases. There was significant structural damage to LSECs in the NASH model, accompanied by remarkable functional changes of LSECs with 174 DEGs (156 upregulated and 18 downregulated genes). The functions of these DEGs were mainly enriched in the inflammatory reactions and immune responses. Nine specifically expressed hub genes were identified. Among them, CCL4 and ITGAX showed the most significant correlation with NASH, with AUROC of 0.77 and 0.86, respectively. The protein-protein interaction network, mRNA-miRNA interaction network, and ceRNA network were further predicted. LSECs show significant structural damage and functional changes in NASH. The LSEC-related DEGs, such as CCL4 and ITGAX, might be promising biomarkers as well as potential treatment targets for NASH.

References

Knolle P, Schmitt E, Jin S, Germann T, Duchmann R, Hegenbarth S . Induction of cytokine production in naive CD4(+) T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells. Gastroenterology. 1999; 116(6):1428-40. DOI: 10.1016/s0016-5085(99)70508-1. View

Kleiner D, Brunt E, Wilson L, Behling C, Guy C, Contos M . Association of Histologic Disease Activity With Progression of Nonalcoholic Fatty Liver Disease. JAMA Netw Open. 2019; 2(10):e1912565. PMC: 6784786. DOI: 10.1001/jamanetworkopen.2019.12565. View

Younossi Z, Koenig A, Abdelatif D, Fazel Y, Henry L, Wymer M . Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2015; 64(1):73-84. DOI: 10.1002/hep.28431. View

Kita Y, Takamura T, Misu H, Ota T, Kurita S, Takeshita Y . Metformin prevents and reverses inflammation in a non-diabetic mouse model of nonalcoholic steatohepatitis. PLoS One. 2012; 7(9):e43056. PMC: 3445596. DOI: 10.1371/journal.pone.0043056. View

Cai J, Zhang X, Li H . The Role of Innate Immune Cells in Nonalcoholic Steatohepatitis. Hepatology. 2019; 70(3):1026-1037. DOI: 10.1002/hep.30506. View

Barker K, Park H, Phan Q, Xu L, Homayouni R, Rogers P . Transcriptome profile of the vascular endothelial cell response to Candida albicans. J Infect Dis. 2008; 198(2):193-202. DOI: 10.1086/589516. View

Li J, Liu S, Zhou H, Qu L, Yang J . starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res. 2013; 42(Database issue):D92-7. PMC: 3964941. DOI: 10.1093/nar/gkt1248. View

Zhao N, Dang H, Ma L, Martin S, Forgues M, Ylaya K . Intratumoral γδ T-Cell Infiltrates, Chemokine (C-C Motif) Ligand 4/Chemokine (C-C Motif) Ligand 5 Protein Expression and Survival in Patients With Hepatocellular Carcinoma. Hepatology. 2020; 73(3):1045-1060. PMC: 9175512. DOI: 10.1002/hep.31412. View

Winkler M, Staniczek T, Kurschner S, Schmid C, Schonhaber H, Cordero J . Endothelial GATA4 controls liver fibrosis and regeneration by preventing a pathogenic switch in angiocrine signaling. J Hepatol. 2020; 74(2):380-393. DOI: 10.1016/j.jhep.2020.08.033. View

10.

Krishnan M, Kd A, Park J, Arjunan V, Marques F, Bermudez A . Genomic Analysis of Vascular Invasion in HCC Reveals Molecular Drivers and Predictive Biomarkers. Hepatology. 2020; 73(6):2342-2360. PMC: 8115767. DOI: 10.1002/hep.31614. View

11.

Wang Y, Zhang Y, Liu Y, Xu J, Liu Y . Gut-Liver Axis: Liver Sinusoidal Endothelial Cells Function as the Hepatic Barrier in Colitis-Induced Liver Injury. Front Cell Dev Biol. 2021; 9:702890. PMC: 8322652. DOI: 10.3389/fcell.2021.702890. View

12.

Hammoutene A, Rautou P . Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease. J Hepatol. 2019; 70(6):1278-1291. DOI: 10.1016/j.jhep.2019.02.012. View

13.

Fujimoto D, Kuwabara T, Hata Y, Umemoto S, Kanki T, Nishiguchi Y . Suppressed ER-associated degradation by intraglomerular cross talk between mesangial cells and podocytes causes podocyte injury in diabetic kidney disease. FASEB J. 2020; 34(11):15577-15590. DOI: 10.1096/fj.202000078RR. View

14.

Frades I, Andreasson E, Mato J, Alexandersson E, Matthiesen R, Martinez-Chantar M . Integrative genomic signatures of hepatocellular carcinoma derived from nonalcoholic Fatty liver disease. PLoS One. 2015; 10(5):e0124544. PMC: 4439034. DOI: 10.1371/journal.pone.0124544. View

15.

Wang J, Yang L, Liang F, Chen Y, Yang G . Integrin alpha x stimulates cancer angiogenesis through PI3K/Akt signaling-mediated VEGFR2/VEGF-A overexpression in blood vessel endothelial cells. J Cell Biochem. 2019; 120(2):1807-1818. DOI: 10.1002/jcb.27480. View

16.

Wang Y, Liu Y . Neutrophil-Induced Liver Injury and Interactions Between Neutrophils and Liver Sinusoidal Endothelial Cells. Inflammation. 2021; 44(4):1246-1262. DOI: 10.1007/s10753-021-01442-x. View

17.

Szklarczyk D, Gable A, Nastou K, Lyon D, Kirsch R, Pyysalo S . The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2020; 49(D1):D605-D612. PMC: 7779004. DOI: 10.1093/nar/gkaa1074. View

18.

Hilscher M, Sehrawat T, Arab J, Zeng Z, Gao J, Liu M . Mechanical Stretch Increases Expression of CXCL1 in Liver Sinusoidal Endothelial Cells to Recruit Neutrophils, Generate Sinusoidal Microthombi, and Promote Portal Hypertension. Gastroenterology. 2019; 157(1):193-209.e9. PMC: 6581607. DOI: 10.1053/j.gastro.2019.03.013. View

19.

Baker S, Baker R, Liu W, Nowak N, Zhu L . Role of alcohol metabolism in non-alcoholic steatohepatitis. PLoS One. 2010; 5(3):e9570. PMC: 2833196. DOI: 10.1371/journal.pone.0009570. View

20.

Poltorak M, Schraml B . Fate mapping of dendritic cells. Front Immunol. 2015; 6:199. PMC: 4418393. DOI: 10.3389/fimmu.2015.00199. View