MiR-146a-5p suppresses activation and proliferation of hepatic stellate cells in nonalcoholic fibrosing steatohepatitis through directly targeting Wnt1 and Wnt5a

Abstract

Nonalcoholic fibrosing steatohepatitis is a uniform process throughout nonalcoholic fatty liver disease (NAFLD). MicroRNAs (miRNAs) have been suggested to modulate cellular processes in liver diseases. However, the functional role of miRNAs in nonalcoholic fibrosing steatohepatitis is largely unclear. In this study, we systematically analyzed the hepatic miRNAs by microarray analysis in nonalcoholic fibrosing steatohepatitis in C57BL/6J mice induced by methionine-choline deficient (MCD) diet. We identified 19 up-regulated and 18 down-regulated miRNAs in liver with fibrosis. Among these dysregulated miRNAs, miR-146a-5p was the most significant down-regulated miRNA. Luciferase activity assay confirmed that Wnt1 and Wnt5a were both the target genes of miR-146a-5p. Hepatic miR-146a-5p was down-regulated in fibrosing steatohepatitis, but its target genes Wnt1 and Wnt5a and their consequent effectors α-SMA and Col-1 were significantly up-regulated. In addition, miR-146a-5p was downregulated, whilst Wnt1 and Wnt5a were up-regulated in the activated primary hepatic stellate cells (HSCs) compared to the quiescent primary HSCs. Overexpression of miR-146a-5p in HSCs inhibited HSC activation and proliferation, which concomitant with the decreased expressions of Wnt1, Wnt5a, α-SMA and Col-1. In conclusion, miR-146a-5p suppresses activation and proliferation of HSCs in the progress of nonalcoholic fibrosing steatohepatitis through targeting Wnt1 and Wnt5a and consequent effectors α-SMA and Col-1.

MicroRNA-30a Suppresses the Activation of Hepatic Stellate Cells by Inhibiting Epithelial-to-Mesenchymal Transition

“…A growing body of evidence suggests that miR-30a is down-regulated in fibrotic livers and acts as a key regulator in myocardial fibrosis and peritoneal fibrosis [19-21]. It has been demonstrated that miR-30a can ameliorate hepatic fibrosis through suppressing Beclin-mediated autophagy [22].…”

MicroRNA‐30a ameliorates hepatic fibrosis by inhibiting Beclin1‐mediated autophagy

“…Du et al . 13 identified 18 down‐regulated and 19 up‐regulated miRNAs in fibrotic livers, of which miR‐30a was down‐regulated in a NASH model in C57BL/6 mice, and studies have reported that miR‐30a is a key regulator of myocardial fibrosis 14 and peritoneal fibrosis 15. Peng et al .…”

Dysregulation of hepatic microRNA expression profiles with Clonorchis sinensis infection

“…Activation and migration of resident HSCs within the hepatic space of Disse play important roles in hepatic fibrosis, and miRNAs have been found to play essential roles in HSC differentiation and proliferation. The results of this study showed that miR-146a-5p, which is reported to suppress activation and proliferation of HSCs through directly targeting of the Wnt1 and Wnt5a genes [20], was differently expressed in the liver. miR-335, which is known to downregulate tenascin-C expression, inhibit HSC migration, and reduce the activities of α-SMA and collagen type I [21], was downregulated in the liver of rats infected with C. sinensis .…”