Nuclear receptors: action, functions, and roles in disease

1.RORpha和Gamma：维甲酸相关的孤儿受体a和g(RORA和RORC)是核受体超家族的成员。为了确定RORA和C的生理功能，对RORA和C功能缺陷的小鼠进行了分析。RORA和RORC在免疫系统中有几个重要的功能。一系列RORC反向激动剂被证明能抑制IL-17启动子的激活，并逆转与银屑病相关的表型效应，这表明它们可能在银屑病的治疗中有用。此外，还发现ROR表达水平的降低与黑色素瘤恶性程度的增加有关。此外，在小鼠模型中，RORT反向激动剂可预防肺中性粒细胞增多和过敏性呼吸道高反应性，而ROR则可预防血管紧张素II诱导的心肌肥大和心力衰竭。 最近，我们还发现了一些维生素D3羟基代谢物可以与RORA和RORC相互作用，并可以作为反向激动剂发挥作用，从而确定了维生素D介导其生理功能的另一种机制。此外，我们还发现D3衍生物可以作为LXRs、RXRs、NURR1和PPARa的激动剂。所有这些受体都在炎症中发挥作用，并可能介导D3衍生物的抗炎和抗癌作用。其中一些D3衍生物可能在治疗炎症性疾病和癌症方面有用。 我们培育了JAZF1 KO小鼠，并表明这些小鼠不太容易患上肝脏脂肪变性，并减少了高脂饮食小鼠肝脏中的脂肪堆积和炎症。对这些小鼠肝脏的RNA-Seq分析发现，许多基因(Deg)在WT和KO小鼠的肝脏中差异表达。对这些DEG的通路分析发现了几条在JAZF1 KO肝脏中下调的代谢途径，并为JAZF1 KO小鼠降低脂肪变性的易感性提供了机制。质谱仪分析鉴定了几种属于JAZF1转录复合体的蛋白质，并包括几种参与基因表达转录激活的蛋白质。

I. RORalpha and gamma: The retinoid-related orphan receptor a and g (RORa and RORc) are members of the nuclear receptor superfamily. To identify the physiological functions of RORa and c, mice deficient in RORa and c function were analyzed. RORa and RORc have several important functions in the immune system. A series of RORc inverse agonists were shown to inhibit the activation of the IL-17 promoter and reverse the phenotypic effects associated with psoriasis suggesting that they may be useful in the treatment of this disease. In addition a relationship has been found between decreased level of ROR expression and increased malignancy of melanoma. Moreover, a RORt inverse agonist protects against pulmonary neutrophilia and allergic airway hyperresponsiveness, while ROR protects against angiotensin II-induced cardiac hypertrophy and heart failure in mouse models. Recently, we also showed that also a number of vitamin D3 hydroxy metabolites can interact with RORa and RORc and can function as inverse agonists thereby identifying an alternative mechanism by which vitamin D can mediate its physiological functions. In addition, we showed that D3 derivatives can functions as agonists for LXRs, RXRs, NURR1, and PPARa. All these receptors have a role in inflammation and may mediate the anti-inflammatory and anti-cancer effects of D3 derivatives. Some of these D3 derivatives might be useful in the treatment of inflammatory disease and cancer. II. We generated JAZF1 KO mice and shown that these mice are less susceptible to develop hepatic steatosis and reduces lipid accumulation and inflammation in the liver of mice fed a high fat diet. RNA-Seq analysis of livers from these mice identified many genes (DEGs) that were differentially expressed in livers from WT and KO mice. Pathway analysis of these DEGs identified several metabolic pathways that were down-regulated in JAZF1 KO liver and provided a mechanism for the reduced susceptibility to steatosis in JAZF1 KO mice. Mass spec analysis identified several proteins that are part of the JAZF1 transcription complex and included several proteins involved in mediating transcriptional activation of gene expression.