Abstract
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-β) and lipopolyssacharide (LPS), two major drivers of liver fibrosis and inflammation, induce miR-942 expression in HSCs via Smad2/3 respective NF-κB/p50 binding to the miR-942 promoter. Mechanistically, the induced miR-942 degrades BAMBI mRNA in HSCs, thereby sensitizing the cells for fibrogenic TGF-β signaling and also partly mediates LPS-induced proinflammatory HSC fate. In conclusion, the TGF-β 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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Abbreviations
- α-SMA:
-
α-Smooth muscle actin
- BAMBI:
-
BMP and activin membrane-bound inhibitor
- BSA:
-
Bovine serum albumin
- ChIP:
-
Chromatin immunoprecipitation
- ECM:
-
Extracellular matrix
- HSC:
-
Hepatic stellate cell
- hHSC:
-
Primary human HSC
- KCs:
-
Kupffer cells
- LPS:
-
Lipopolysaccharide
- LSECs:
-
Liver sinusoidal endothelial cells
- mRNA:
-
Messenger RNA
- PBS:
-
Phosphate-buffered saline
- TGFβ:
-
Transforming growth factor β
- UTR:
-
Untranslated regions
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Acknowledgements
This work was mainly supported by The National Natural Science Foundation of China (No. 81673788 to C. Liu), Peak discipline of Colleges and universities in Shanghai (No. A-U151902 to C Liu), and Research Project of Putuo Hospital Fund (No. 2016204B to C Liu & No. 2017207A to WT M). Federal Ministry of Education and Research grant ‘LiSyM’ (Grant PTJ-FKZ: 031L0043 to S Dooley). National Institutes of Health Grant (No. R01DK085252, R21AA025841 to E. Seki) and Winnick Research award from Cedars-Sinai Medical Center (to E. Seki). Xinglin Scholar of Shanghai University of Traditional Chinese Medicine (to C Liu) and Shanghai Municipal Commission of Health and Family Plan Fund (No. 20144Y0185 to L Wu). We thank Lingzhi Lian and honghui Wen (Department of Pathology, Putuo Hospital) for technical support with fibrotic stage analysis.
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CL, ES and SD conceived and designed the experiments, and discussed the results. LT, DXS and WTM carried out all experiments. XFW, YQY, LW, KP, DYX and ZJ helped with the human liver biopsy specimen. ZCN supported with data presentation and in manuscript revision. CL and ES wrote the manuscript, which was read, edited and approved by all the authors.
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Tao, L., Xue, D., Shen, D. et al. MicroRNA-942 mediates hepatic stellate cell activation by regulating BAMBI expression in human liver fibrosis. Arch Toxicol 92, 2935–2946 (2018). https://doi.org/10.1007/s00204-018-2278-9
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DOI: https://doi.org/10.1007/s00204-018-2278-9