Comprehensive analysis of endoplasmic reticulum-related and secretome gene expression profiles in the progression of non-alcoholic fatty liver disease

Abstract

Endoplasmic reticulum (ER) is the principal organelle for protein synthesis, such as hepatokines and transmembrane proteins, and is critical for maintaining physiological function. Dysfunction of ER is associated with metabolic disorders. However, the role of ER homeostasis as well as hepatokines in the progression of non-alcoholic fatty liver disease (NAFLD) remains to be elucidated. Here we comprehensively analyzed the RNA-seq profiles of liver biopsies from 206 NAFLD patients and 10 controls from dataset GSE135251. The co-expression modules were constructed based on weighted gene co-expression network analysis and six co-expression modules were identified, of which brown module stood out to be significantly associated with fibrosis stage and NAFLD activity score (NAS). Subsequently, cytoscape with cytoHubba plugin was applied to identify hub genes in the brown module. GO and KEGG enrichment analysis of the top 20 hub genes were performed and showed the involvement of extracellular matrix formation, collagen synthesis and decomposition, etc. Further, the expression of the top 20 hub genes were found to be a consistent increasing trend as the fibrosis stages and NAS increased, which have been validated both in HFD fed and HFHC fed mice. Among these genes, THY1, PTGDS, TMPRSS3, SPON1, COL1A2, RHBDF1, COL3A1, COL5A1, COL1A1 and IGFBP7 performed well in distinguishing fibrosis stage, while COL1A2, COL3A1, THY1, RHBDF1 and COL1A2 exhibited good capacity to discriminate NAS. Besides, RHBDF1, COL3A1, QSOX1, STING1, COL5A1, IGFBP7, COL4A2, COL1A1, FKBP10 and COL1A2 also showed a strong power in the diagnosis of NAFLD. In addition, COL1A1, COL1A2, COL3A1, COL8A2, IGFBP7, PGF, PTGDS, SPON1, THY1 and TIMP1 were identified as secretome genes from the top 20 hub genes. Of them, circulated THY1 and collagen III level were validated to be significantly elevated in the MCD diet-induced mice. Thus, we provided a systemic view on understanding the pathological roles and mechanisms of ER as well as secretome in NAFLD progression. THY1, COL1A1, COL1A2, COL3A1 and RHBDF1 could be served as candidate biomarkers to evaluate the progression of NAFLD.

Identification of Basement Membrane Genes and Related Molecular Subtypes in Nonalcoholic Fatty Liver Disease

“…According to the KEGG and GO analysis results of DEGs and susceptibility gene module, ECM seems to play an important role in the development of NAFLD. This finding is consistent with several previous studies 22 23 24 . BMs themselves are a unique form of ECM that mainly exist under endothelial and epithelial cells 3 .…”

“…As a member of the extracellular glycoprotein family, LAMC3 is involved in a variety of biological processes, including maintenance of tissue structure, tissue differentiation and migration, as well as tumor invasion and metastasis [33]. Several previous studies on NAFLD-based transcriptome sequencing have also suggested that COL5A1 and LAMC3 might play important roles in NAFLD [22,24].…”

Integrative network-based analysis on multiple Gene Expression Omnibus datasets identifies novel immune molecular markers implicated in non-alcoholic steatohepatitis

“…Thanks to the rapid development of high-throughput sequencing technology and gene chip technology, more and more researchers are actively pursuing molecular markers using data mining and analysis of sequencing data or gene chips to the diagnosis and treatment of disease ( 19 , 43 , 44 ). In our study, we analyzed gene expression profiles of NASH patients and normal controls from five independent GEO data sets.…”

“…Integrating multi-omics approaches including genomics, transcriptomics, proteomics and metabolomics have provided additional insights (12)(13)(14)(15), which may not be elucidated by genomics analysis alone. In addition, previous bioinformatics analyses in cross-sectional studies have facilitated the exploration of potential biomarkers related to NAFLD/NASH (16)(17)(18)(19). However, for complex disease trait, the comprehensive molecular characterization of NASH are still not entirely deciphered.…”

Unveiling the pathogenesis of non-alcoholic fatty liver disease by decoding biomarkers through integrated single-cell and single-nucleus profiles

“…This protein plays a critical role in inflammation and is implicated in the initiation and progression of cancer. Studies suggested that both QSOX1 and IL1RAP hold promise as potential biomarkers of NAFLD or obesity (17, 18).…”