Liver fibrosis is a major endpoint of patients with chronic
liver diseases. The molecular mechanisms behind
liver fibrosis remain largely unknown. Many studies have indicated the role of
microRNA (
miRNA) in hepatic
tumorigenesis. But the role of
miRNA in
liver fibrosis is little known. Activated hepatic stellate cells (HSCs) can secret
extracellular matrix proteins (ECM) and are the major contributors to
liver fibrosis/
cirrhosis. Here, a microarray assay of quiescent and
transforming growth factor β1 (TGF-β1) activated HSCs indicated that miR-98 might play a crucial role in
liver fibrosis. We found that miR-98 was significantly downregulated in activated HSCs. miR-98 overexpression inhibited HSCs activation. Furthermore, we hypothesized that miR-98 regulated hepatic
leukemia factor (HLF) expression by binding to the
3' UTR of its
mRNA directly, as evidenced by
luciferase reporter assay. HLF overexpression increased HSCs activation by inducing
hypoxia inducible factor-1 alpha (HIF-1α) expression, resulting in the activation of TGF-β/Smad2/3 signaling pathway. Besides, low expression of miR-98 was also found in liver tissues from various fibrotic murine models, including
carbon tetrachloride (CCl4), bile duct
ligation (BDL), and high-fat diet (HFD)-induced
liver fibrosis. miR-98 overexpression in vivo by ago-miR-98 injection could attenuate CCl4-, BDL-, and HFD-induced murine hepatic
fibrosis. Meanwhile, miR-98 overexpression suppressed HLF expression and reduced
fibrosis marker expression. Collectively, our study demonstrates that miR-98 suppress HSCs activation by targeting HLF directly and interacting with HIF-1α/TGF-β/Smad2/3 signaling pathway, which may be an effective therapeutic target for
liver fibrosis.