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Long Non-Coding RNAs Involved in Progression of Non-Alcoholic Fatty Liver Disease to Steatohepatitis.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and is characterized by different stages varying from benign fat accumulation to non-alcoholic steatohepatitis (NASH) that may progress to cirrhosis and liver cancer. In recent years, a regulatory role of long non-coding RNAs (lncRNAs) in NAFLD has emerged. Therefore, we aimed to characterize the still poorly understood lncRNA contribution to disease progression. Transcriptome analysis in 60 human liver samples with various degrees of NAFLD/NASH was combined with a functional genomics experiment in an in vitro model where we exposed HepG2 cells to free fatty acids (FFA) to induce steatosis, then stimulated them with tumor necrosis factor alpha (TNFα) to mimic inflammation. Bioinformatics analyses provided a functional prediction of novel lncRNAs. We further functionally characterized the involvement of one novel lncRNA in the nuclear-factor-kappa B (NF-κB) signaling pathway by its silencing in Hepatoma G2 (HepG2) cells. We identified 730 protein-coding genes and 18 lncRNAs that responded to FFA/TNFα and associated with human NASH phenotypes with consistent effect direction, with most being linked to inflammation. One novel intergenic lncRNA, designated lncTNF, was 20-fold up-regulated upon TNFα stimulation in HepG2 cells and positively correlated with lobular inflammation in human liver samples. Silencing lncTNF in HepG2 cells reduced NF-κB activity and suppressed expression of the NF-κB target genes A20 and NFKBIA. The lncTNF we identified in the NF-κB signaling pathway may represent a novel target for controlling liver inflammation.

SUBMITTER: Atanasovska B

PROVIDER: S-EPMC8394311 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Long Non-Coding RNAs Involved in Progression of Non-Alcoholic Fatty Liver Disease to Steatohepatitis.

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