Cholesterol metabolite, 5-cholesten-3β-25-diol-3-sulfate, promotes hepatic proliferation in mice.
Cholesterol metabolite, 5-cholesten-3β-25-diol-3-sulfate, promotes hepatic proliferation in mice.
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DOI：
10.1016/j.jsbmb.2012.06.001
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发表时间：
2012-11
影响因子：
4.1
通讯作者：
Ren, Shunlin
中科院分区：
文献类型：
--
作者：
Zhang, Xin;Bai, Qianming;Kakiyama, Genta;Xu, Leyuan;Kim, Jin Kyung;Pandak, William M., Jr.;Ren, Shunlin
关键词：
氧固醇是众所周知的肝X受体（LXR）的生理配体。氧化固醇，25-羟基胆固醇（25 HC）和27-羟基胆固醇作为LXR的内源性配体，通过LXR信号通路抑制细胞增殖。最近的研究表明，硫酸化氧化甾醇，5-胆甾烯-3 β，25-二醇3-硫酸酯（25 HC 3S）作为LXR拮抗剂，在脂质生物合成中起与氧化甾醇相反的作用。本研究旨在探讨25 HC 3S对小鼠肝脏增殖的影响及其机制。给药后，25 HC 3S在循环中的半衰期为48 h，并广泛分布于小鼠组织中。ProfilerTM PCR阵列和RTqPCR分析显示，通过氧固醇磺基转移酶的过表达产生的外源或内源25 HC 3S可诱导25 HC 3S的表达。（SULT 2B 1b）加25 HC给药显著上调Wt 1、Pcna、cMyc、细胞周期蛋白A、FoxM 1b、和CDC 25 b在肝脏中以剂量依赖性方式，而实质上降低-调控细胞周期阻滞基因Chek 2和凋亡基因Apaf 1的表达。无论是外源性或内源性管理的25 HC 3S显着诱导肝DNA复制的PCNA标记指数的免疫染色测量，并与LXR反应基因，如ABCA 1和SREBP-1c的表达减少。合成的LXR激动剂T0901317有效地阻断25 HC 3S诱导的肝增殖。结论：25 HC 3S可能是肝细胞增殖的有效调节剂，并且氧固醇硫酸化可能代表通过灭活LXR信号传导的肝增殖的新的调节途径。
Oxysterols are well known as physiological ligands of Liver X receptors (LXRs). Oxysterols, 25-Hydroxycholesterol (25HC) and 27-hydroxycholesterol as endogenous ligands of LXRs, suppress cell proliferation via LXRs signaling pathway. Recent reports have shown that sulfated oxysterol, 5-cholesten-3β, 25-diol 3-sulfate (25HC3S) as LXRs antagonist, plays an opposite direction to oxysterols in lipid biosynthesis. The present report was to explore the effect and mechanism of 25HC3S on hepatic proliferation in vivo. Following administration, 25HC3S had a 48 h half life in the circulation and widely distributed in mouse tissues. Profiler™ PCR array and RTqPCR analysis showed that either exogenous or endogenous 25HC3S generated by overexpression of oxysterol sulfotransferase (SULT2B1b) plus administration of 25HC significantly up-regulated the proliferation gene expression of Wt1, Pcna, cMyc, cyclin A, FoxM1b, and CDC25b in a dose-dependent manner in liver while substantially down-regulating the expression of cell cycle arrest gene Chek2 and apoptotic gene Apaf1. Either exogenous or endogenous administration of 25HC3S significantly induced hepatic DNA replication as measured by immunostaining of the PCNA labeling index and was associated with reduction in expression of LXR response genes, such as ABCA1 and SREBP-1c. Synthetic LXR agonist T0901317 effectively blocked 25HC3S-induced hepatic proliferation. Conclusions: 25HC3S may be a potent regulator of hepatocyte proliferation and oxysterol sulfation may represent a novel regulatory pathway in liver proliferation via inactivating LXR signaling.
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影响因子：
5.1
作者：
Coughtrie, MWH;Sharp, S;Innes, NP
通讯作者：
Innes, NP
影响因子：
8.7
作者：
CORSINI, A;VERRI, D;FUMAGALLI, R
通讯作者：
FUMAGALLI, R
DOI：
10.1073/pnas.0404297101
发表时间：
2004-08-03
影响因子：
11.1
作者：
Chen, GX;Liang, GS;Brown, MS
通讯作者：
Brown, MS
影响因子：
5.9
作者：
Cain, K
通讯作者：
Cain, K
DOI：
10.1073/pnas.96.1.266
发表时间：
1999-01-05
影响因子：
11.1
作者：
Janowski, BA;Grogan, MJ;Mangelsdorf, DJ
通讯作者：
Mangelsdorf, DJ