MicroRNA-214 promotes hepatic stellate cell activation and liver fibrosis by suppressing Sufu expression

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.

Twist1-induced miR-199a-3p promotes liver fibrosis by suppressing caveolin-2 and activating TGF-β pathway

“…14 Conversely, miR-214 promotes HSC activation and liver fibrosis by suppressing Sufu expression. 15 In addition, multiple miRNAs (i.e. miR-122, miR-101, miR-133a, miR-221/222, miR-181b and miR-19b) participate in controlling HSC activation and liver fibrosis.…”

miR‐193a/b‐3p relieves hepatic fibrosis and restrains proliferation and activation of hepatic stellate cells

“…Increasing evidence has demonstrated the pivotal roles of miRNAs in the pathogenesis of liver fibrosis . A research by Ma et al reported that miR‐214 promoted the development of liver fibrosis via inducing the activation of HSCs . In addition, miR‐873‐5p has been demonstrated to be a marker for liver fibrosis and regulate the early stages of liver fibrosis .…”

Alpha-1 antitrypsin deficient individuals have circulating extracellular vesicles with profibrogenic cargo

“…Additionally, miRNAs were correlated with various clinical characteristics in ZZ individuals such as HSCs activation, brosis and cirrhosis, and HCC which shows the possibility of using EVs as a potential source of biomarkers for early diagnosis of disease progression. Importantly, we identi ed that of the 44 miRNAs whose levels change in the plasma EVs of AATD individuals, 5 which were higher in AATD individuals (miR-125a, miR-125b1, miR-125b2, miR-128 and miR-130b) and 1 lower (miR-6809) appear to play important roles in liver brosis (41)(42)(43)(44)(45). A large body of evidence supports the implication of the miR-125 family and miR-130b (46) in different liver diseases, including ALF (47), non-alcoholic fatty liver disease (48), cholestasis (49), and HCC (50).…”