Abstract
BackgroundmiRNAs are non-coding RNAs that regulate gene expression in a wide range of biological contexts, including a variety of diseases. The present study clarified the role of miR-214-5p in hepatic fibrogenesis using human clinical tissue samples, livers from rodent models, and cultured hepatic stellate cells.MethodsThe expression of miR-214-5p and genes that are involved in liver fibrosis were analyzed in hepatitis C virus-infected human livers, rodent fibrotic livers, a human stellate cell line (LX-2), and the cells from intact mouse livers using real-time PCR. The effect of miR-214-5p overexpression in LX-2 cells on cell function was investigated. Twist-1 expression in the liver tissues of mouse models and primary-cultured stellate cells was also analyzed.ResultsmiR-214-5p was upregulated in human and mouse livers in a fibrosis progression–dependent manner. miR-214-5p expression increased during the culture-dependent activation of mouse primary stellate cells and was significantly higher in stellate cells than in hepatocytes. The overexpression of miR-214-5p in LX-2 cells increased the expression of fibrosis-related genes, such as matrix metalloproteinase (MMP)-2, MMP-9, α-smooth muscle actin, and transforming growth factor (TGF)-β1. TGF-β stimulation induced miR-214-5p in LX-2 cells. Twist-1 was increased in fibrotic mouse livers and induced during mouse stellate cell activation.ConclusionmiR-214-5p may play crucial roles in the activation of stellate cells and the progression of liver fibrosis. Twist-1 may regulate miR-214-5p expression in the liver, particularly in stellate cells.
Highlights
MiRNAs are non-coding RNAs that regulate gene expression in a wide range of biological contexts, including a variety of diseases
MiR-214 expression in a mouse model of liver fibrosis Liver fibrosis was induced by feeding mice a methionine- and choline-deficient diet (MCDD) for 5 or 15 weeks and compared with mice fed a methionine- and choline-control diet (MCCD)
The mRNAs of liver fibrosis factors, such as α-smooth muscle actin (α-SMA), the type 1 collagen alpha 1 chain (Col1a1), platelet-derived growth factor receptor (PDGFR)-β, Transforming growth factor (TGF)-β1, fibronectin (FN) 1, discoidin domain receptor (DDR) 2, and β1 integrin (ITGB1), were upregulated in the livers of MCDD-fed mice compared to MCCD-fed mice (Figure 2B). miR-214-5p expression was significantly higher in the livers of MCDD-fed mice than in control mice (2.1-fold, P < 0.01 at 5 weeks; and 4.8-fold, P < 0.01 at 15 weeks) (Figure 2C)
Summary
MiRNAs are non-coding RNAs that regulate gene expression in a wide range of biological contexts, including a variety of diseases. The present study clarified the role of miR-214-5p in hepatic fibrogenesis using human clinical tissue samples, livers from rodent models, and cultured hepatic stellate cells. Liver fibrosis is characterized by an abnormal accumulation of extracellular matrix (ECM) components, including types I and III collagen, laminin, and proteoglycans, in the liver parenchyma [2,3]. Transforming growth factor (TGF)-β, which is produced and released by activated macrophages and platelets at the site of local inflammation, is considered to play a primary role in the fibrotic process [3]. Disse’s space, store vitamin A and act as tissue-specific pericytes under physiological conditions - undergo activation and transformation into myofibroblast-like cells that express α-smooth muscle actin (α-SMA) during persistent inflammation. The activated stellate cells become an additional source of TGF-β and a principal producer of ECM components. The detailed molecular mechanisms of TGF-β production in these cells have not been determined [4]
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