Retinoic acid-related Orphan Receptor γ (RORγ): connecting sterol metabolism to regulation of the immune system and autoimmune disease.
Retinoic acid-related Orphan Receptor γ (RORγ): connecting sterol metabolism to regulation of the immune system and autoimmune disease.
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DOI：
10.1016/j.cotox.2018.01.005
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发表时间：
2018-04
影响因子：
4.6
通讯作者：
Kang HS
中科院分区：
文献类型：
--
作者：
Jetten AM;Takeda Y;Slominski A;Kang HS
胆固醇及其代谢物是生物活性脂质，其与各种蛋白质和信号传导途径相互作用并调节其活性，所述蛋白质和信号传导途径参与控制各种生理和病理过程。近年来的研究表明，视黄酸相关孤儿受体RORα和γ是配体依赖性核受体超家族的成员，对多种甾醇具有广泛的结合特异性。几种胆固醇中间体和代谢物作为RORα和RORγ的天然配体发挥作用，并作为激动剂或反向激动剂发挥作用。改变细胞中固醇代谢物的水平或类型的胆固醇稳态的变化可以增强或抑制ROR转录活性，其随后导致由ROR调节的生理过程的变化，包括各种免疫应答和代谢途径。因此，这可能会负面或正面影响ROR所涉及的病理学，例如自身免疫性疾病、炎症、代谢综合征、癌症和几种神经系统疾病。研究最多的是胆固醇代谢、RORγt活性及其对Th 17分化和自身免疫性疾病的调节之间的联系。在几种实验性自身免疫性疾病模型中，在RORγ缺陷小鼠中Th 17依赖性炎症显著减弱的发现，启动了对ROR调节剂的研究，从而鉴定了许多小分子量RORγ反向激动剂。反向激动剂抑制Th 17分化和IL-17产生，并防止自身免疫。总之，这些研究表明，RORγt可能在几种（炎性）疾病的管理中提供有吸引力的治疗靶点。
Cholesterol and its metabolites are bioactive lipids that interact with and regulate the activity of various proteins and signaling pathways that are implicated in the control of a variety of physiological and pathological processes. Recent studies revealed that retinoic acid-related orphan receptors, RORα and γ, members of the ligand-dependent nuclear receptor superfamily, exhibit quite a wide binding specificity for a number of sterols. Several cholesterol intermediates and metabolites function as natural ligands of RORα and RORγ and act as agonists or inverse agonists. Changes in cholesterol homeostasis that alter the level or type of sterol metabolites in cells, can either enhance or inhibit ROR transcriptional activity that subsequently result in changes in the physiological processes regulated by RORs, including various immune responses and metabolic pathways. Consequently, this might negatively or positively impact pathologies, in which RORs are implicated, such as autoimmune disease, inflammation, metabolic syndrome, cancer, and several neurological disorders. Best studied are the links between cholesterol metabolism, RORγt activity, and their regulation of Th17 differentiation and autoimmune disease. The discovery that Th17-dependent inflammation is significantly attenuated in RORγ-deficient mice in several experimental autoimmune disease models, initiated a search for ROR modulators that led to the identification of a number of small molecular weight RORγ inverse agonists. The inverse agonists suppress Th17 differentiation and IL-17 production and protect against autoimmunity. Together, these studies suggest that RORγt may provide an attractive therapeutic target in the management of several (inflammatory) diseases.
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影响因子：
4.6
作者：
Ačimovič J;Goyal S;Košir R;Goličnik M;Perše M;Belič A;Urlep Ž;Guengerich FP;Rozman D
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影响因子：
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影响因子：
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通讯作者：
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影响因子：
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