Multiomics contributes to the discovery of common factors in alcohol- and hepatitis B virus-related liver fibrosis.

BACKGROUND

Liver fibrosis due to alcohol consumption or chronic hepatitis B virus (HBV)-related liver disease is a major challenge for global health. Despite the different mechanisms of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows a shared pattern. Our research aimed to identify key factors associated with shared patterns of alcohol- or HBV-related liver fibrosis.

METHODS

Liver samples from three alcohol-related fibrosis patients, six HBV-related fibrosis patients, and five hepatic hemangioma patients were collected and grouped. Transcriptome and proteome sequencing were used to identify differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in alcohol- or HBV-related liver fibrosis hepatic stellate cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to understand the functions of the DEGs or DEPs. Immunohistochemistry analysis, dual-luciferase reporter assays, Western blotting, real-time quantitative polymerase chain reaction, and chromatin immunoprecipitation were used to investigate annexin A2 (ANXA2) function and regulatory mechanisms.

RESULTS

Transcriptomic analysis revealed 744 overlapping upregulated DEGs in patients with alcohol- or HBV-related liver fibrosis. GO and KEGG analyses revealed that 744 DEGs were involved in vasculature development and the extracellular matrix organization pathway. Proteomics revealed 99 overlapping upregulated DEPs in patients with alcohol- or HBV-related liver fibrosis. GO and KEGG analyses revealed that 99 DEPs were involved in phagosome and neutrophil degranulation. Integration of the transcriptome and proteome revealed that ANXA2 and perilipin 1 (PLIN1) might be key factors for the progression of liver fibrosis. Biochemical analysis revealed that ANXA2 positively regulates the process of liver fibrosis, whereas PLIN1 negatively regulates the process of liver fibrosis. Furthermore, the mechanisms by which ANXA2 is regulated by the NF-κB pathway during alcohol consumption and by the Janus kinase-signal transducer/activator of transcription 3 pathway during HBV infection are well proved.

CONCLUSIONS

Our findings demonstrate that ANXA2 and PLIN1 are key factors involved in the progression of both alcohol- and HBV-related liver fibrosis, and further clarify the distinct regulatory mechanisms of ANXA2 mediated by the NF-κB pathway in alcohol-induced fibrosis and in HBV-related fibrosis.