Journal
MOLECULAR THERAPY-NUCLEIC ACIDS
Volume 12, Issue -, Pages 57-66Publisher
CELL PRESS
DOI: 10.1016/j.omtn.2018.04.016
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Funding
- National Key R&D Program of China [2017YFA0504400]
- National Natural Science Foundation of China [91440205, 81572400]
- Natural Science Foundation of Guangdong Province [2017A030313107]
- Fundamental Research Funds for the Central Universities [171gjc32]
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miR-125b is frequently dysregulated in different diseases. Activation of hepatic stellate cells (HSCs) is a critical event during liver fibrogenesis. However, the function and its underlying mechanism of miR-125b in HSC activation and liver fibrosis are still unknown. Here, we showed that miR-125b was upregulated in HSCs, but not in hepatocytes, during hepatic fibrogenesis in vivo and upon culture activation in vitro. Inhibition of miR-125b suppressed the expression of profibrogenic genes in culture-activated primary HSCs and reduced the basal and transforming growth factor beta (TGF-beta)-induced alpha-smooth muscle actin (alpha-SMA) expression and cell contraction of the immortalized HSC cell line. In contrast, ectopic expression of miR-125b promoted a-SMA expression and HSC contraction. Moreover, antagonizing miR-125b in vivo significantly alleviated liver fibrosis in CCl4-treated mice. Mechanistically, overexpression of miR-125b in HSCs enhanced RhoA activity by directly targeting StAR-related lipid transfer (START) domain containing 13 (Stard13), a RhoA-specific GTPase-activating protein, whereas knockdown of miR-125b abrogated RhoA activation. Furthermore, inhibition of RhoA or its downstream molecules, Mrtf-A and Srf, attenuated the miR-125b-induced alpha-SMA expression and HSC contraction. Therefore, our findings identify a miR-125b-Stard13-RhoA-alpha-SMA signaling cascade in HSCs and highlight its importance in hepatic fibrosis.
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