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Expansion of macrophage and liver sinusoidal endothelial cell subpopulations during non-alcoholic steatohepatitis progression.

ABSTRACT: Liver non-parenchymal cells (NPCs) play a critical role in the progression of non-alcoholic steatohepatitis (NASH). We aimed to explore the heterogeneity of NPCs and identify NASH-specific subpopulations contributing to NASH progression. Through single-cell RNA sequencing, we uncovered a proinflammatory subpopulation of Itgad^hi/Fcrl5^hi macrophages with potential function of modulating macrophage accumulation and promoting NASH development. We also identified subpopulations of Egr1^hi and Ly6a^hi liver sinusoidal endothelial cells (LSECs), which might participate in pathological angiogenesis and inflammation regulation. The Itgad^hi/Fcrl5^hi macrophages, Egr1^hi LSECs, and Ly6a^hi LSECs emerged in the early stage and expanded significantly along with pathological progression of liver injury during NASH. Cell-cell interactions between hepatic stellate cells (HSCs) and Itgad^hi/Fcrl5^hi macrophages, Egr1^hi LSECs or Ly6a^hi LSECs were enhanced in NASH liver. Our results revealed that expansion of Itgad^hi/Fcrl5^hi macrophages, Egr1^hi LSECs or Ly6a^hi LSECs was strongly associated with NASH severity, suggesting these subpopulations might be involved in NASH progression.

SUBMITTER: Shen Z

PROVIDER: S-EPMC10131129 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Expansion of macrophage and liver sinusoidal endothelial cell subpopulations during non-alcoholic steatohepatitis progression.

Shen Zhenyang Z Shen Bo B Dai Weiming W Zhou Cui C Luo Xin X Guo Yuecheng Y Wang Junjun J Xu Xianjun X Sun Zhongshang Z Cai Xiaobo X Dong Hui H Lu Lungen L

iScience 20230405 5

Liver non-parenchymal cells (NPCs) play a critical role in the progression of non-alcoholic steatohepatitis (NASH). We aimed to explore the heterogeneity of NPCs and identify NASH-specific subpopulations contributing to NASH progression. Through single-cell RNA sequencing, we uncovered a proinflammatory subpopulation of Itgad<sup>hi</sup>/Fcrl5<sup>hi</sup> macrophages with potential function of modulating macrophage accumulation and promoting NASH development. We also identified subpopulations ...[more]

PMID: 37124414

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Project description:BackgroundNon-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Autophagy plays a vital role in NAFLD development and progression. We aimed to establish a novel autophagy-related gene (ARG) signature as a therapeutic target in NAFLD patients based on high-throughput sequencing data.MethodsARGs obtained from the HAMdb and high-sequencing data obtained from the Gene Expression Omnibus (GEO) database were analyzed to identify differentially expressed ARGs (DEARGs) between normal and NASH tissues. Then, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to explore potential biological and pathological functions of DEARGs. The protein-protein interaction (PPI) network of the DEARGs was established through the STRING website, and visualized by Cytoscape. In addition, hub genes were validated by an independent dataset GSE89632. Finally, we performed Gene Set Variation Analysis (GSVA) pathway-related analysis to identify the pivotal signaling pathways and genes for the progression of non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH).ResultsA total of 76 DEARGs were identified in the GSE126848 dataset, of which 45 genes were upregulated and 31 genes were downregulated. GO analysis showed that the biological functions of DEARGs focused primarily on autophagy, cellular response to external stimulus, fibroblast proliferation, late endosome, and ubiquitin protein ligase binding. KEGG pathway analysis showed that these DEARGs were mainly involved in the apoptosis, PI3K-Akt signaling pathway, and estrogen signaling pathway. Among DEGs, 9 most closely related genes were identified from the PPI network. Furthermore, NOS3, IGF1, VAMP8, FOS, and HMOX1 were verified in the GSE89632 dataset. At last, the MAPK signal pathway was identified as important pathway, and JUN was identified as a key gene involved in the progression from NAFL to NASH.ConclusionThis study may provide credible molecular biomarkers in terms of screening and diagnosis for NAFLD. Meanwhile, it also serves as a basis for exploring the molecular mechanisms underlying the progression of NAFL to NASH.

Project description:IntroductionNon-alcoholic steatohepatitis (NASH) may progress to more advanced liver disease. This study aimed to characterize NASH progression and mortality in the Medicare population.MethodsPatients with NASH in 100% Medicare fee-for-service claims accrued from 2015-2021 who were ≥ 66 years old at index diagnosis, continuously enrolled for ≥ 12 months prior to and ≥ 6 months following index (unless death), and had no evidence of other causes of liver disease were included. Diagnosis codes defined severity states: non-cirrhotic NASH, compensated cirrhosis (CC), decompensated cirrhosis (DCC), hepatocellular carcinoma (HCC), and liver transplant (LT). Survival analyses of disease progression and mortality were conducted for each state and by year of progression (Y1-5). Cox proportional hazards models assessed risk factors of worsening disease.ResultsMean age and follow-up were 72.2 and 2.8 years in 14,806 unique patients (n = 12,990 NASH; 1899 CC; 997 DCC; 209 HCC; 140 LT). Progression rates were highest for patients with CC (11-37% for Y1-5), followed by DCC (3-18%), NASH (3-12%), and HCC (2-4%). Mortality rates were highest for patients with HCC (41-85% for Y1-5), followed by DCC (41-76%), LT (7-33%), CC (6-26%), and NASH (2-12%). Patients with any disease progression had a 5-year mortality rate more than double that of patients without progression (41% vs. 16%). Delayed progression from NASH was associated with lower mortality risk; the 5-year mortality rate was 26% lower for patients with progression in Y2 vs. Y1 (32% vs. 43%) and further decreased for progression in Y3-Y5. Risk factors included age, nursing home use, congestive heart failure, coagulopathy, fluid/electrolyte disorders, and unexplained weight loss.ConclusionMedicare patients ≥ 66 years with NASH experience high risk of disease progression associated with increased mortality rates. Slower disease progression is associated with lower mortality rates, suggesting that therapies that can delay or prevent NASH progression may reduce morbidity and mortality.

Dataset Information

Expansion of macrophage and liver sinusoidal endothelial cell subpopulations during non-alcoholic steatohepatitis progression.

Publications

Expansion of macrophage and liver sinusoidal endothelial cell subpopulations during non-alcoholic steatohepatitis progression.

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