Abstract
MicroRNAs (miRNAs) have been demonstrated to modulate cellular processes in the liver. However, the role of miRNAs in liver fibrosis is poorly understood. Because the activation of hepatic stellate cells (HSCs) is a pivotal event in the initiation and progression of hepatic fibrosis, we investigate the differential expression of miRNAs in activated and quiescent rat HSCs by microarray analysis and find that miR-214 (miR-214-3p) is significantly upregulated during HSC activation. Moreover, the robust induction of miR-214 is correlated with liver fibrogenesis in carbon tetrachloride (CCl4)-treated rats and mice, high-fat diet-induced non-alcoholic steatohepatitis in mice, and cirrhosis in humans. We identify that miR-214 expression is driven by the helix–loop–helix transcription factor Twist1 via the E-box element. The increased miR-214 inhibits the expression of suppressor-of-fused homolog (Sufu), a negative regulator of the Hedgehog signaling pathway, thereby contributing to HSC activation to promote the accumulation of fibrous extracellular matrix and the expression of profibrotic genes in HSCs and LX2 cells. Furthermore, miR-214 expression is inversely correlated with the expression of Sufu in clinical cirrhosis samples. To explore the clinical potential of miR-214, we inject antagomiR-214 oligos into mice to induce hepatic fibrosis. The knockdown of miR-214 in vivo enhances Sufu expression and reduces fibrosis marker expression, which ameliorates liver fibrosis in mice. In conclusions, the Twist1-regulated miR-214 promotes the activation of HSC cells through targeting Sufu involved in the Hedgehog pathway and participates in the development of hepatic fibrosis. Hence, the knockdown of miR-214 expression may be a promising therapeutic strategy for liver fibrosis.
Highlights
Many chronic liver diseases, such as hepatitis B or C infection, alcoholic liver disease, non-alcoholic steatohepatitis (NASH), and autoimmune hepatitis, can lead to hepatic fibrosis, which is characterized by the excessive (HSCs) are the major producers of extracellular matrix (ECM), which play an important role in liver fibrogenesis
Results miR-214 expression is increased during hepatic stellate cells (HSCs) activation To identify the miRNAs involved in liver fibrosis, we isolated primary HSCs from normal rat livers and cultured them
The activation of HSCs was further confirmed by the increased mRNA abundance of HSC activation markers including α-smooth muscle actin (α-SMA), collagen type 1-α1 (COL1α1), and fibronectin (FN) (Fig. 1b) and upregulated protein levels of αSMA and FN (Fig. 1c)
Summary
Many chronic liver diseases, such as hepatitis B or C infection, alcoholic liver disease, non-alcoholic steatohepatitis (NASH), and autoimmune hepatitis, can lead to hepatic fibrosis, which is characterized by the excessive (HSCs) are the major producers of ECM, which play an important role in liver fibrogenesis. These cells are quiescent in healthy livers and are stimulated by profibrotic cytokines, including transforming growth factor-β (TGF-β), platelet-derived growth factor C (PDGF-C), and connective tissue growth factor[2, 3].
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