Department of Medicine, Virginia Commonwealth University/Veterans Affairs McGuire Medical Center, 1201 Broad Rock Boulevard, Richmond, VA 23249, United States.
J Steroid Biochem Mol Biol. 2012 Nov;132(3-5):262-70. doi: 10.1016/j.jsbmb.2012.06.001. Epub 2012 Jun 23.
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.
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.
氧化固醇是众所周知的肝脏 X 受体 (LXRs) 的生理配体。氧化固醇，25-羟胆固醇 (25HC) 和 27-羟胆固醇作为 LXRs 的内源性配体，通过 LXRs 信号通路抑制细胞增殖。最近的报道表明，硫酸化氧化固醇，5-胆甾烯-3β-25-二醇-3-硫酸盐 (25HC3S) 作为 LXRs 的拮抗剂，在脂质生物合成中发挥与氧化固醇相反的作用。本报告旨在探讨 25HC3S 对体内肝增殖的影响及其机制。给药后，25HC3S 在循环中的半衰期为 48 小时，广泛分布于小鼠组织中。Profiler™PCR 阵列和 RTqPCR 分析表明，外源性或内源性 25HC3S 通过过表达氧化固醇硫酸转移酶 (SULT2B1b) 加用 25HC 产生，以剂量依赖性方式显著上调肝脏中 Wt1、Pcna、cMyc、细胞周期蛋白 A、FoxM1b 和 CDC25b 的增殖基因表达，而显著下调细胞周期阻滞基因 Chek2 和凋亡基因 Apaf1 的表达。外源性或内源性给予 25HC3S 均可显著诱导肝脏 DNA 复制，如 PCNA 标记指数的免疫染色所示，并与 LXR 反应基因如 ABCA1 和 SREBP-1c 的表达减少相关。合成 LXR 激动剂 T0901317 可有效阻断 25HC3S 诱导的肝增殖。
25HC3S 可能是肝细胞增殖的有效调节剂，氧化固醇硫酸化可能通过失活 LXR 信号代表肝脏增殖的新调节途径。
