Abstract
Hydroxysteroid sulfotransferase 2B1b (SULT2B1b) sulfates cholesterol and oxysterols. Hepatic oval cells (HOCs), thought to be progenitor cells, can be triggered in chemically injured livers. The present study focused on the role of SULT2B1b in HOC proliferation after liver injury. Our experiments revealed that the expression of SULT2B1b was increased dramatically in a chemical-induced liver injury model, mainly in HOCs. Upon challenge with a hepatotoxic diet containing 0.1 % 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), SULT2B1−/− mice presented alleviated liver injury and less HOC proliferation compared with wild-type (WT) mice, and these findings were verified by serum analysis, histopathology, immunofluorescence staining, RNA-seq, and Western blotting. HOCs derived from SULT2B1−/− mice showed lower proliferative capability than those from WT mice. SULT2B1b overexpression promoted growth of the WB-F344 hepatic oval cell line, whereas SULT2B1b knockdown inhibited growth of these cells. The IL-6/STAT3 signaling pathway also was promoted by SULT2B1b. Liquid chromatography and mass spectrometry indicated that the levels of 22-hydroxycholesterol, 25-hydroxycholesterol, and 24,25-epoxycholesterol were higher in the DDC-injured livers of SULT2B1−/− mice than in livers of WT mice. The above oxysterols are physiological ligands of liver X receptors (LXRs), and SULT2B1b suppressed oxysterol-induced LXR activation. Additional in vivo and in vitro experiments demonstrated that LXR activation could inhibit HOC proliferation and the IL-6/STAT3 signaling pathway, and these effects could be reversed by SULT2B1b. Our data indicate that upregulation of SULT2B1b might promote HOC proliferation and aggravate liver injury via the suppression of oxysterol-induced LXR activation in chemically induced mouse liver injury.
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Abbreviations
- 22HC:
-
22-Hydroxycholesterol
- 25HC:
-
25-Hydroxycholesterol
- 24,25HC:
-
24,25-Epoxycholesterol
- ABCG5 and ABCG8:
-
ATP-binding cassette transporters G5 and G8
- ANIT:
-
α-Naphthylisothiocyanate
- CCl4 :
-
Carbon tetrachloride
- CDE:
-
Choline-deficient ethionine-supplemented diet
- CIS:
-
Cytokine-inducible SH2-containing protein
- CK19:
-
Cytokeratin 19
- c-myc:
-
Myelocytomatosis oncogene
- DDC:
-
3,5-Diethoxycarbonyl-1,4-dihydrocollidine
- EpCAM:
-
Epithelial cell adhesion molecule
- gp130:
-
Glycoprotein 130
- IL-6:
-
Interleukin 6
- LC-MS:
-
Liquid chromatography and mass spectrometry
- LXR:
-
Liver X receptor
- PH:
-
Partial hepatectomy
- PCNA:
-
Proliferating cell nuclear antigen
- PKM2:
-
Mitogen-activated protein kinase-2
- qRT-PCR:
-
Quantitative real-time polymerase chain reaction
- SOCS3:
-
Suppressor of cytokine signaling 3
- STAT3:
-
Signal transducer and activator of transcription 3
- SULT2B1:
-
Hydroxysteroid sulfotransferase 2B1
- SULT2B1−/− :
-
SULT2B1-deficient
- TAA:
-
Thioacetamide
- WT:
-
Wild-type
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Acknowledgments
We thank Dr. Shunlin Ren for generously providing SULT2B1 adenovirus vectors (Ad-SULT2B1). We further thank Dr. Chih-hao Lee for providing expression vector for Gal4-DNA binding domain (DBD)-LXRα ligand binding domain (LBD) fusion protein and Gal4 luciferase reporter vector. This work was supported by the National Natural Science Foundation of China (NSFC 81270497, NSFC 81572713), Shanghai Municipal Natural Science Foundation (12ZR1403000), and Natural Science Foundation of Ningxia Province of China (NX14074). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Wang, Z., Yang, X., Chen, L. et al. Upregulation of hydroxysteroid sulfotransferase 2B1b promotes hepatic oval cell proliferation by modulating oxysterol-induced LXR activation in a mouse model of liver injury. Arch Toxicol 91, 271–287 (2017). https://doi.org/10.1007/s00204-016-1693-z
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DOI: https://doi.org/10.1007/s00204-016-1693-z