Journal
ARCHIVES OF TOXICOLOGY
Volume 92, Issue 9, Pages 2935-2946Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-018-2278-9
Keywords
TGF-beta signaling; HSCs; Viral hepatitis; Liver fibrosis
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Funding
- National Natural Science Foundation of China [81673788]
- Peak discipline of Colleges and universities in Shanghai [A-U151902]
- Research Project of Putuo Hospital Fund [2016204B, 2017207A]
- Federal Ministry of Education and Research grant 'LiSyM' [PTJ-FKZ: 031L0043]
- National Institutes of Health [R01DK085252, R21AA025841]
- Cedars-Sinai Medical Center
- Shanghai Municipal Commission of Health and Family Plan Fund [20144Y0185]
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MicroRNA (miRNA)-mediated gene regulation contributes to liver pathophysiology, including hepatic stellate cell (HSC) activation and fibrosis progression. Here, we investigated the role of miR-942 in human liver fibrosis. The expression of miR-942, HSC activation markers, transforming growth factor-beta pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI), as well as collagen deposition, were investigated in 100 liver specimens from patients with varying degree of hepatitis B virus (HBV)-related fibrosis. Human primary HSCs and the immortalized cell line (LX2 cells) were used for functional studies. We found that miR-942 expression was upregulated in activated HSCs and correlated inversely with BAMBI expression in liver fibrosis progression. Transforming growth factor beta (TGF-beta) and lipopolyssacharide (LPS), two major drivers of liver fibrosis and inflammation, induce miR-942 expression in HSCs via Smad2/3 respective NF-kappa B/p50 binding to the miR-942 promoter. Mechanistically, the induced miR-942 degrades BAMBI mRNA in HSCs, thereby sensitizing the cells for fibrogenic TGF-beta signaling and also partly mediates LPS-induced proinflammatory HSC fate. In conclusion, the TGF-beta and LPS-induced miR-942 mediates HSC activation through downregulation of BAMBI in human liver fibrosis. Our study provides new insights on the molecular mechanism of HSC activation and fibrosis.
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