MicroRNA-146b regulates hepatic stellate cell activation via targeting of KLF4

Background. We previously identified miR-146b as being up-regulated during the development of hepatic fibrosis using deep sequencing technology and gene expression analysis. However, the roles and related mechanisms of miR-146b in hepatic stellate cells (HSCs), which are involved in fibrogenesis and fibrosis, have not been elucidated.

We report that miR-146b expression was increased in TGF-ß1-treated HSCs. TGF- ß1 enhanced α-SMA and COL1A1 protein expression in HSCs and stimulated proliferation of these cells compared with cells transfected with inhibitor NC. Conversely, miR-146b knock-down decreased α-SMA and COL1A1 expression and inhibited HSC proliferation. In addition, we found that miR-146b specifically regulated the translation of Krüppel-like factor 4 (KLF4) by targeting its 3' untranslated region. Forced expression of KLF4 inhibited TGF- ß1-induced enhancement of α-SMA and COL1A1 expression in HSCs, as well as proliferation of these cells. Moreover, miR-146b expression was negatively associated with KLF4 expression but positively associated with expression of α-SMA and COL1A1 during hepatic fibrosis.

Our findings demonstrate the participation of miR-146b as a novel upstream effector of HSC activation via direct targeting of KLF4. Thus, targeted transfer of miR-146b into HSCs could be a useful strategy for the treatment of hepatic fibrosis.