Upregulation of hydroxysteroid sulfotransferase 2B1b promotes hepatic oval cell proliferation by modulating oxysterol-induced LXR activation in a mouse model of liver injury
Upregulation of hydroxysteroid sulfotransferase 2B1b promotes hepatic oval cell proliferation by modulating oxysterol-induced LXR activation in a mouse model of liver injury
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在肝损伤小鼠模型中，羟基类固醇磺基转移酶 2B1b 的上调通过调节氧甾醇诱导的 LXR 激活促进肝卵圆细胞增殖
DOI：
10.1007/s00204-016-1693-z
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发表时间：
2016
影响因子：
6.1
通讯作者：
Li Xiaobo
中科院分区：
文献类型：
--
作者：
Wang Zhengyang;Yang Xiaoming;Chen Liang;Zhi Xiuling;Lu Hanyu;Ning Yanxia;Yeong Joe;Chen Sifeng;Yin Lianhua;Wang Xinhong;Li Xiaobo
羟基类固醇磺基转移酶2B1b(SULT2B1b)可硫化胆固醇和氧化甾醇。肝卵圆细胞(HOCs)被认为是前体细胞，可以在化学损伤的肝脏中被触发。本研究旨在探讨SULT2B1b在肝损伤后HOC增殖中的作用。我们的实验表明，在化学诱导的肝损伤模型中，SULT2B1b的表达显著增加，主要是在HOCs。与野生型(WT)小鼠相比，给予含0.1%3，5-二乙氧基甲酰-1，4-二氢可乐定(DDC)的肝毒性饲料攻击后，SULT2B1−/−小鼠的肝损伤减轻，细胞增殖减少，并通过血清分析、组织病理学、免疫荧光染色、rna-seq和Western blotting进行了验证。−/−小鼠来源的HOCs的增殖能力低于WT小鼠。SULT2B1b过表达促进WB-F344肝卵圆细胞系的生长，而SULT2B1b基因敲除则抑制这些细胞的生长。SULT2B1b对IL-6/STAT3信号通路也有促进作用。−/−小鼠肝脏中22-羟基胆固醇、25-羟基胆固醇和24，25-环氧胆固醇的含量明显高于WT小鼠。上述氧固醇是肝X受体(LXRs)的生理配体，SULT2B1b抑制氧固醇诱导的LXR激活。另外，体内和体外实验表明，LXR激活可以抑制HOC增殖和IL-6/STAT3信号通路，这些作用可被SULT2B1b逆转。我们的数据表明，SULT2B1b的上调可能通过抑制氧固醇诱导的LXR激活而促进HOC增殖，加重肝损伤。
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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影响因子：
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作者：
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影响因子：
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作者：
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