MicroRNA dynamics and networks to liver fibrosis-related genes during hepatic stellate cell activation by agalactosyl IgG and transforming growth factor-β1

Abstract

The pathogenic effects of agalactosyl IgG on activating hepatic stellate cells (HSCs) and promoting liver fibrogenesis have been previously reported. However, the dynamics of miRNAome and their association with fibrosis-related genes during HSC activation by agalactosyl IgG remain unclear. We performed small RNA sequencing in human LX-2 HSCs at different time points after agalactosyl IgG treatment. The dynamic change in HSC miRNAome induced by agalactosyl IgG was compared with that induced by normal IgG and transforming growth factor (TGF)-β1 plus normal IgG to exclude the effects caused by IgGs. The differentially expressed miRNA (DEmiRNA) profiles between HSCs induced by IgG agalactosylation and TGF-β1 were strongly correlated; the number of upregulated DEmiRNAs remained stable, whereas that of downregulated DEmiRNAs increased from day 5. Disease ontology analyses revealed that 33 DEmiRNAs were associated with 5 or more categories of liver diseases. In total, 52 fibrosis-related genes were mapped to 183 DEmiRNAs in HSCs activated by IgG agalactosylation or TGF-β1; 37 upregulated and 64 downregulated of these DEmiRNAs were correlated with decreased expression and increased expression of 9 and 24 liver fibrosis-related genes, respectively. Gene ontology analyses revealed that these genes were involved in collagen organization, extracellular matrix assembly, growth factor activity and receptor binding, SMAD protein complex and signaling transduction, fatty acid and lipid biosynthesis, and mesenchymal cell proliferation. In conclusion, this study characterizes the dynamic miRNAome and its association with fibrosis-related genes in HSC caused by IgG agalactosylation and TGF-β1, offering insights into potential therapeutic targets for liver fibrosis.

Keywords: Glycosylation; Hepatic stellate cells; IgG; Liver fibrosis; miRNA.