Abstract
Long non-coding RNAs (lncRNAs) have recently emerged as inflammation-associated biological molecules with a specific role in the progression of liver fibrosis conditions including non-alcoholic steatohepatitis (NASH). The aim of this study was to elucidate the effects of lncRNA nuclear enriched abundant transcript 1 (NEAT1), microRNA-129-5p (miR-129-5p), and paternally expressed gene 3 (PEG3) on the biological activities of hepatic stellate cells (HSCs) subjected to NASH. First, microarray-based analysis revealed upregulated PEG3 in NASH. Liver tissues from mice fed a methionine–choline-deficient (MCD) diet exhibited increased expression of NEAT1 and PEG3 along with lower miR-129-5p expression. A series of in vitro and in vivo assays were then performed on HSCs after transfection with shPEG3, miR-129-5p mimic, or treatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of the nuclear factor-kappa B (NF-κB) signaling pathway. Results confirmed the alleviated fibrosis by restoring miR-129-5p, while depleting PEG3 or NEAT1, as evidenced by the inactivation of HSCs. To sum up, NEAT1 can bind specifically to miR-129-5p and consequently regulate miR-129-5p and PEG3 expression in relation to the HSC activation occurring in NASH. Thus, NEAT1-targeted inhibition against miR-129-5p presents a promising therapeutic strategy for the treatment of NASH.
Highlights
Non-alcoholic steatohepatitis (NASH) is a condition that is marked by hepatic inflammation and necrosis accompanied by fat storage and fatty deposition in liver parenchymal cells, which accounts for 25% of the causes of hepatocellular carcinoma (HCC) (Charrez et al, 2016)
It was reported that nuclear enriched abundant transcript 1 (NEAT1) could affect HCC through interaction with microRNA-129-5p (Fang et al, 2017), which has been proposed as a biomarker of liver fibrosis responsible for the activation of hepatic stellate cells (HSCs) and collagen synthesis (Chen et al, 2018)
MiR-129-5p/Paternally expressed gene 3 (PEG3) Axis May Be Involved in Liver Fibrosis of non-alcoholic steatohepatitis (NASH)
Summary
Non-alcoholic steatohepatitis (NASH) is a condition that is marked by hepatic inflammation and necrosis accompanied by fat storage and fatty deposition in liver parenchymal cells, which accounts for 25% of the causes of hepatocellular carcinoma (HCC) (Charrez et al, 2016). NEAT1 plays an important role in a rat model of non-alcoholic fatty liver disease (NAFLD) involving the mammalian target of rapamycin/S6 kinase beta-1 signaling pathway (Wang, 2018). It was reported that NEAT1 could affect HCC through interaction with microRNA-129-5p (miR-129-5p) (Fang et al, 2017), which has been proposed as a biomarker of liver fibrosis responsible for the activation of hepatic stellate cells (HSCs) and collagen synthesis (Chen et al, 2018). We probed in detail the functioning of a NEAT1/miR129-5p/PEG3 axis in NASH and identified the underlying mechanisms with the NF-κB signaling pathway, which may guide research toward much-needed new approaches for the treatment for NASH
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