MicroRNA29a Reverts the Activated Hepatic Stellate Cells in the Regression of Hepatic Fibrosis through Regulation of ATPase H⁺ Transporting V1 Subunit C1.

Fei Jing,Xin-Yi Xu,Yan Geng,Zheng-Hong Xu,Jin-Song Shi,Hong-Yu Xu

doi:10.3390/ijms20040796

Fei Jing, Xin-Yi Xu + Show 4 more

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https://doi.org/10.3390/ijms20040796

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Abstract

Activated hepatic stellate cells (aHSCs) play a key role in liver fibrosis. During the regression of fibrosis, aHSCs are transformed into inactivated cells (iHSCs), which are quiescent lipid-containing cells and express higher levels of lipid-related genes, such as peroxisome proliferators-activated receptors gamma (PPARγ). Here, we investigated the role of MicroRNA29a (Mir29a) in the resolution of liver fibrosis. Mir29a and lipid-related genes were up-regulated after the recovery of CCl4-induced liver fibrosis in mice. PPARγ agonist rosiglitazone (RSG) promoted de-differentiation of aHSCs to iHSCs and up-regulated MIR29a expression in a human HSC cell line LX-2. MIR29a mimics in vitro promoted the expression of lipid-related genes, while decreased the expression of fibrosis-related genes. MIR29a inhibitor showed the reverse effects. ATPase H+ transporting V1 subunit C1 (Atp6v1c1) was increased in liver fibrosis, while down-regulated after the recovery in mice, and negatively regulated by MIR29a in LX-2 cells. Knockdown of ATP6V1C1 by siRNA decreased alpha-smooth muscle actin (α-SMA) and increased lipid-related genes expression. Simultaneous addition of MIR29a mimics and ATP6V1C1 siRNA further increased RSG promoted expression of lipid-related proteins in vitro. Collectively, MIR29a plays an important role during the trans-differentiation of aHSCs in the resolution of liver fibrosis, in part, through regulation of ATP6V1C1.

Highlights

Fibrosis diseases cause serious harm to human health [1], such as pulmonary fibrosis, cirrhosis, glomerulosclerosis, myelofibrosis, and hypertrophic scars [2]
We focused on investigating the role of MIR29a in the resolution of liver fibrosis
By quantitative real-time PCR, we found that α-Sma and Col1 were significantly up-regulated (Figure 1A,B), while the expression of Mir29a was decreased in liver tissues after 28 days with CCl4 treatment, as compared to controls (CTL) (Figure 1C)

Summary

Introduction

Fibrosis diseases cause serious harm to human health [1], such as pulmonary fibrosis, cirrhosis, glomerulosclerosis, myelofibrosis, and hypertrophic scars [2]. Liver fibrosis is the liver’s wound healing response to a variety of external injuries, which can cause cirrhosis and even hepatocellular carcinoma. The study of the molecular mechanisms in the resolution of liver fibrosis may be essential for prevention and treatment. Quiescent hepatic stellate cells (qHSCs) are present in normal liver and store retinoids in large amounts of lipid droplets [7]. QHSCs are activated by cytokines released by immune cells and hepatocytes, and gradually lose their retinoid-filled lipid droplets [8]. Genetic tracing studies revealed that HSCs are the main ECM producer during hepatic fibrogenesis [11,12]

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