Kim Woo-Kyun, Meliton Vicente, Park Kye Won, Hong Cynthia, Tontonoz Peter, Niewiadomski Pawel, Waschek James A, Tetradis Sotirios, Parhami Farhad
Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
Mol Endocrinol. 2009 Oct;23(10):1532-43. doi: 10.1210/me.2008-0453. Epub 2009 Jul 16.
Hedgehog (Hh) signaling is indispensable in embryonic development, and its dysregulated activity results in severe developmental disorders as shown by genetic models of naturally occurring mutations in animal and human pathologies. Hh signaling also functions in postembryonic development and adult tissue homeostasis, and its aberrant activity causes various human cancers. Better understanding of molecular regulators of Hh signaling is of fundamental importance in finding new strategies for pathway modulation. Here, we identify liver X receptors (LXRs), members of the nuclear hormone receptor family, as previously unrecognized negative regulators of Hh signaling. Activation of LXR by specific pharmacological ligands, TO901317 and GW3965, inhibited the responses of pluripotent bone marrow stromal cells and calvaria organ cultures to sonic Hh, resulting in the inhibition of expression of Hh-target genes, Gli1 and Patched1, and Gli-dependent transcriptional activity. Moreover, LXR ligands inhibited sonic Hh-induced differentiation of bone marrow stromal cells into osteoblasts. Elimination of LXRs by small interfering RNA inhibited ligand-induced inhibition of Hh target gene expression. Furthermore, LXR ligand did not inhibit Hh responsiveness in mouse embryonic fibroblasts that do not express LXRs, whereas introduction of LXR into these cells reestablished the inhibitory effects. Daily oral administration of TO901317 to mice after 3 d significantly inhibited baseline Hh target-gene expression in liver, lung, and spleen. Given the importance of modulating Hh signaling in various physiological and pathological settings, our findings suggest that pharmacological targeting of LXRs may be a novel strategy for Hh pathway modulation.
刺猬信号通路（Hh）在胚胎发育中不可或缺，其活性失调会导致严重的发育障碍，动物和人类病理学中自然发生的基因突变的遗传模型已证明了这一点。Hh信号通路在胚胎后发育和成年组织稳态中也发挥作用，其异常活性会导致各种人类癌症。更好地了解Hh信号通路的分子调节因子对于寻找新的通路调节策略至关重要。在此，我们确定核激素受体家族成员肝X受体（LXRs）为Hh信号通路先前未被认识的负调节因子。用特异性药理配体TO901317和GW3965激活LXR，可抑制多能骨髓基质细胞和颅骨器官培养物对音猬因子（sonic Hh）的反应，导致Hh靶基因Gli1和Patched1的表达以及Gli依赖的转录活性受到抑制。此外，LXR配体抑制音猬因子诱导的骨髓基质细胞向成骨细胞的分化。用小干扰RNA消除LXR可抑制配体诱导的Hh靶基因表达的抑制作用。此外，LXR配体对不表达LXR的小鼠胚胎成纤维细胞的Hh反应性没有抑制作用，而将LXR导入这些细胞可恢复抑制作用。给小鼠每日口服TO901317，3天后可显著抑制肝脏、肺和脾脏中Hh靶基因的基础表达。鉴于在各种生理和病理环境中调节Hh信号通路的重要性，我们的研究结果表明，对LXR进行药理靶向可能是调节Hh通路的一种新策略。
