Effect of miR-183-5p on Cholestatic Liver Fibrosis by Regulating Fork Head Box Protein O1 Expression

Abstract

Liver fibrosis is a common pathological feature of end-stage liver disease and has no effective treatment. MicroRNAs (miRNAs) have been found to modulate gene expression in liver disease. But the potential role of miRNA in hepatic fibrosis is still unclear. The objective of this research is to study the potential mechanism and biological function of miR-183-5p in liver fibrosis. In this study, we used high-throughput sequencing to find that miR-183-5p is upregulated in human fibrotic liver tissues. In addition, miR-183-5p was upregulated both in rat liver fibrosis tissue induced by bile-duct ligation (BDL) and activated LX-2 cells (human hepatic stellate cell line) according to the result of quantitative real-time PCR (RT-qPCR). Moreover, the inhibition of miR-183-5p alleviated liver fibrosis, decreased the fibrotic biomarker levels in vitro and in vivo, and led toLX-2 cell proliferation inhibition and, apoptosis induction. The result of dual-luciferase assay revealed that miR-183-5p suppressed fork head box protein O1 (FOXO1) expression by binding to its 3′UTR directly. Next, we used lentivirus to overexpress FOXO1 in LX-2 cells, and we found that overexpression of FOXO1 reversed the promotion of miR-183-5p on liver fibrosis, reducing the fibrotic biomarker levels inLX-2 cells, inhibitingLX-2 cell proliferation, and promoting apoptosis. Furthermore, overexpression of FOXO1 prevented the activation of the transforming growth factor (TGF)-β signaling pathway in TGF-β1-induced LX-2 cells according to the result of western blotting. In conclusion, the findings showed thatmiR-183-5p might act as a key regulator of liver fibrosis, and miR-183-5p could promote cholestatic liver fibrosis by inhibiting FOXO1 expression through the TGF-β signaling pathway. Thus, inhibition of miR-183-5pmay be a new way to prevent and improve liver fibrosis.

miRNA-ome plasma analysis unveils changes in blood–brain barrier integrity associated with acute liver failure in rats

“…The miR-183-5p was upregulated in BDL-induced liver fibrosis and activated human hepatic stellate cells (LX-2 cell line) [ 97 ]. Accordingly, miR-183-5p inhibition alleviated liver fibrosis and downregulated the expression of related fibrotic biomarkers [ 97 ]. Additionally, miR-183-5p inhibition reduced LX-2 cell proliferation and promoted apoptosis.…”

“…Additionally, miR-183-5p inhibition reduced LX-2 cell proliferation and promoted apoptosis. The results showed that miR-183-5p might act as a key regulator of liver fibrosis, and miR-183-5p could promote cholestatic liver fibrosis through the TGFβ signaling pathway [ 97 ]. Supportively, another study demonstrated upregulation of the miR-183 family in diethylamino ethylamine-induced hepatic fibrosis, suggesting a role in the progression severity of liver fibrosis [ 98 ].…”

Inhibition of Proliferation, Migration, and Invasion of Keloid Fibroblasts By miR-183-5p Through Downregulating EGR1

“…However, each miRNA can regulate numerous genes. The target genes of miR-183-5p include ZEB2, FOXO1, RGS2, and ABAT (Wang et al, 2021;Mo et al, 2022). Moreover, the function of miRNA is also associated with the relative abundance of target genes.…”

Ductular Reaction in Total and Partial Biliary Obstruction in Experimental Settings

“…Studies have shown that the expression level of specific miRNAs changes in the blood serum, peripheral blood mononuclear cells, and the liver tissue itself of patients with chronic liver disease (primary biliary cirrhosis). 79 miRNAs play a critical role in hepatic stem cell activation; for example, miR-183-5p is increased in bile duct ligation-induced liver fibrotic tissue, which in turn activates LX-2 cells (a hematopoietic stem cell line), 80 and miRNA-29a also inhibits bromodomaincontaining protein 4, leading to suppression of hematopoietic stem cell activation and resulting in reduced liver fibrosis. 81 miRNAs play an important role in maintaining bile acid homeostasis.…”