Format

Send to

Choose Destination
Arch Toxicol. 2018 Sep;92(9):2935-2946. doi: 10.1007/s00204-018-2278-9. Epub 2018 Aug 10.

MicroRNA-942 mediates hepatic stellate cell activation by regulating BAMBI expression in human liver fibrosis.

Author information

1
Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 164 Lanxi Rd, Shanghai, 200062, China.
2
Laboratory of Liver Disease, Department of Infectious Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
3
Department of Pathology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
4
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
5
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Steven.Dooley@medma.uni-heidelberg.de.
6
Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. Ekihiro.Seki@cshs.org.
7
Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 164 Lanxi Rd, Shanghai, 200062, China. liucheng0082010@163.com.
8
Laboratory of Liver Disease, Department of Infectious Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China. liucheng0082010@163.com.
9
Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Shanghai, 200062, China. liucheng0082010@163.com.

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.

KEYWORDS:

HSCs; Liver fibrosis; TGF-β signaling; Viral hepatitis

PMID:
30097701
PMCID:
PMC6590087
DOI:
10.1007/s00204-018-2278-9
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center