Abstract
The activation of hepatic stellate cells (HSCs) participates in liver fibrosis, and emerging evidences indicate that microRNAs (miRNAs) are abnormally expressed during HSC activation. However, the potential roles of miRNAs in liver fibrosis still remain elusive. Therefore, this study aimed to investigate the role of miR-199a-3p in liver fibrosis and its underlying mechanism. We found that miR-199a-3p expression was dramatically upregulated during HSC activation in vitro, and during liver fibrogenesis in CCl4-treated rats, and its liver expression was increased in the patients with cirrhosis. By the luciferase assay and RT-qPCR, we revealed that the expression of miR-199a-3p in HSCs was driven by the transcription factor Twist1 which could be further induced by TGF-β treatment. Functional studies showed that inhibition of miR-199a-3p in both human LX2 cells and rat HSCs significantly decreased the expression of fibrotic markers, such as fibronectin and connective tissue growth factor (CTGF), whereas the forced expression of miR-199a-3p exhibited opposite effects, demonstrating the role of miR-199a-3p in promoting HSC activation. Mechanistically, miR-199a-3p plays an important role in TGF-β signalling pathway activation through targeting CAV2 that negatively regulates the expression of transforming growth factor-beta receptor type I (TGFβRI). Importantly, administration of antagomiR-199a-3p in the CCl4-treated mice significantly ameliorated hepatic fibrosis. In conclusion, Twist1-induced miR-199a-3p mediates the activation of HSCs by suppressing CAV2 expression and subsequently increasing TGFβRI expression to promote TGF-β pathway. Our findings highlight the therapeutic potential of miR-199a-3p for hepatic fibrosis.
Highlights
Liver fibrosis is defined as excess deposition of extracellular matrix (ECM) in response to various liver damages and progresses to decompensated cirrhosis or hepatocellular carcinoma (HCC) with limited therapeutic options.[1,2] Activated hepatic stellate cells (HSCs) are considered as the key cell type driving liver fibrosis.[3]
RESULTS miR-199a-3p expression is increased during HSC activation To identify aberrant miRNAs during HSC activation, we firstly isolated rat primary HSCs from healthy livers
The enhanced expression of fibrotic markers including FN, α-smooth muscle actin (α-SMA), pSMAD2/3 and connective tissue growth factor (CTGF) further confirmed the activation of HSCs (Fig. 1b, c)
Summary
Liver fibrosis is defined as excess deposition of extracellular matrix (ECM) in response to various liver damages and progresses to decompensated cirrhosis or hepatocellular carcinoma (HCC) with limited therapeutic options.[1,2] Activated hepatic stellate cells (HSCs) are considered as the key cell type driving liver fibrosis.[3]. Given the lack of curing or reversing treatment for liver fibrosis currently, new insights into the molecular mechanisms controlling HSC activation are essential to discover new effective therapeutic strategies for liver fibrosis.
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