更新于：2024-11-01

NR1D2

更新于：2024-11-01

基本信息

别名

BD73、EAR-1R、Hs.37288

+ [11]

简介

Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner. Integral component of the complex transcription machinery that governs circadian rhythmicity and forms a critical negative limb of the circadian clock by directly repressing the expression of core clock components BMAL1 and CLOCK. Also regulates genes involved in metabolic functions, including lipid metabolism and the inflammatory response. Acts as a receptor for heme which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. Recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers, depending on the nature of the response element. Binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nuclegotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and also negatively regulates the expression of NR1D1. Regulates lipid and energy homeostasis in the skeletal muscle via repression of genes involved in lipid metabolism and myogenesis including: CD36, FABP3, FABP4, UCP3, SCD1 and MSTN. Regulates hepatic lipid metabolism via the repression of APOC3. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). In addition to its activity as a repressor, can also act as a transcriptional activator. Acts as a transcriptional activator of the sterol regulatory element-binding protein 1 (SREBF1) and the inflammatory mediator interleukin-6 (IL6) in the skeletal muscle (By similarity). Plays a role in the regulation of circadian sleep/wake cycle; essential for maintaining wakefulness during the dark phase or active period (By similarity). Key regulator of skeletal muscle mitochondrial function; negatively regulates the skeletal muscle expression of core clock genes and genes involved in mitochondrial biogenesis, fatty acid beta-oxidation and lipid metabolism (By similarity). May play a role in the circadian control of neutrophilic inflammation in the lung (By similarity).

关联

项与 NR1D2 相关的药物

ARN-5187

靶点

自噬蛋白 x NR1D2

作用机制

Autophagy protein inhibitors [+1]

在研机构-

原研机构

Istituto Italiano di Tecnologia

在研适应症-

非在研适应症

肿瘤

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

SR-9009

靶点

NR1D1 x NR1D2

作用机制

NR1D1 刺激剂 [+1]

在研机构-

原研机构

The Salk Institute for Biological Studies

在研适应症-

非在研适应症

肿瘤

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 NR1D2 相关的临床结果

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100 项与 NR1D2 相关的转化医学

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0 项与 NR1D2 相关的专利（医药）

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283

项与 NR1D2 相关的文献（医药）

2024-11-01·Cardiovascular Toxicology

Exploration of Clozapine-Induced Cardiomyopathy and Its Mechanism

Article

作者: Zhang, Shangyu ; Jin, Pengyue ; Yang, Li ; Tang, Renkuan ; Li, Yongguo ; Zeng, Yujie

In this study, by pooling the clinical data of patients who died with a history of long-term clozapine use and by examining their hearts, it was found that long-term clozapine use can lead to cardiomyopathy and that its presentation resembles arrhythmogenic cardiomyopathy (ACM), i.e., it exhibits a predominantly right ventricular fatty infiltration with mild left ventricular damage. The transcriptomic data of rat cardiomyocytes after clozapine intervention were analyzed by transcriptomic approach to explore the causes of clozapine cardiomyopathy. The cause of clozapine cardiomyopathy was then explored by a transcriptomic approach, which revealed that its clozapine action on cardiomyocytes enriched cardiomyocyte-related differential genes in biological processes such as muscle development and response to hypoxia, as well as pathways such as fatty acid metabolism and cellular autophagy. Transcriptomic analysis showed that Egr1, Egr2, ler2, Jun, Mapk9, Nr1d2, Atf3, Bhlhe40, Crem, Cry1, Cry2, Dbp were hub genes for clozapine injury to the myocardium, and that these genes may play an important role in the myocardial ACM-like changes caused by clozapine. Combined with the results of pathological examination and transcriptomic analysis, it can be concluded that the long-term action of clozapine on cardiomyocytes leads to cellular autophagy and subsequent structural remodeling of the heart, and in the remodeling affects fatty acid metabolism, which eventually leads to ACM-like changes.

2024-09-01·Mammalian Genome

Fibroblasts as an in vitro model of circadian genetic and genomic studies

Article

作者: Francia, Marcelo ; De la Hoz, Juan F ; Ophoff, Roel A ; Boltz, Toni ; Bot, Merel ; Boks, Marco ; Kahn, René S

AbstractBipolar disorder (BD) is a heritable disorder characterized by shifts in mood that manifest in manic or depressive episodes. Clinical studies have identified abnormalities of the circadian system in BD patients as a hallmark of underlying pathophysiology. Fibroblasts are a well-established in vitro model for measuring circadian patterns. We set out to examine the underlying genetic architecture of circadian rhythm in fibroblasts, with the goal to assess its contribution to the polygenic nature of BD disease risk. We collected, from primary cell lines of 6 healthy individuals, temporal genomic features over a 48 h period from transcriptomic data (RNA-seq) and open chromatin data (ATAC-seq). The RNA-seq data showed that only a limited number of genes, primarily the known core clock genes such as ARNTL, CRY1, PER3, NR1D2 and TEF display circadian patterns of expression consistently across cell cultures. The ATAC-seq data identified that distinct transcription factor families, like those with the basic helix-loop-helix motif, were associated with regions that were increasing in accessibility over time. Whereas known glucocorticoid receptor target motifs were identified in those regions that were decreasing in accessibility. Further evaluation of these regions using stratified linkage disequilibrium score regression analysis failed to identify a significant presence of them in the known genetic architecture of BD, and other psychiatric disorders or neurobehavioral traits in which the circadian rhythm is affected. In this study, we characterize the biological pathways that are activated in this in vitro circadian model, evaluating the relevance of these processes in the context of the genetic architecture of BD and other disorders, highlighting its limitations and future applications for circadian genomic studies.

2024-08-01·Journal of Thermal Biology

Timing of acute cold exposure determines UCP1 and FGF21 expression - Possible interactions between the thermal environment, thermoregulatory responses, and peripheral clocks

Article

作者: Haugen, Fred ; Ryan, Elin ; Dalen, Knut Tomas ; Chau, Phong Kt

Thermoregulation is synchronized across the circadian cycle to uphold thermal homeostasis. To test if time-of-day matters for the response to environmental cold exposure, mice were acclimated to thermoneutrality (27 °C) for 2 months were subjected acutely (8 h) to cold ambient conditions (15 °C), whereas controls were maintained at thermoneutral conditions. The thermal exposure was tested in separate groups (N = 8) at three distinct time-of-day periods: in the LIGHT phase (L); the DARK phase (D); and a mix of the two (D + L). The magnitude of UCP1 protein and mRNA induction in brown adipose tissue (BAT) in response to acute cold exposure was time-of-day sensitive, peaking in LIGHT, whereas lower induction levels were observed in D + L, and DARK. Plasma levels of FGF21 were induced 3-fold by acute cold exposure at LIGHT and D + L, compared to the time-matched thermoneutral controls, whereas cold in DARK did not cause a significant increase of FGF21 plasma levels. Cold exposure affected, in BAT, the temporal mRNA expression patterns of core circadian clock components: Bmal1, Clock, Per1, Per3, Cry1, Cry2 Nr1d1, and Nr1d2, but in the liver, none of the transcripts were modified. Behavioral assessment using the Thermal Gradient Test (TGT) showed that acute cold exposure reduced cold sensitivity in D + L, but not in DARK. RNA-seq analyses of somatosensory neurons in DRG highlighted the role of the core circadian components in these cells, as well as transcriptional changes due to acute cold exposure. This elucidates the sensory system as a gauge and potential regulator of thermoregulatory responses based on circadian physiology. In conclusion, acute cold exposure elicits time-of-day specific effects on thermoregulatory pathways, which may involve underlying changes in thermal perception. These results have implications for efforts aimed at reducing risks associated with the organization of shift work in cold environments.

项与 NR1D2 相关的新闻（医药）

2022-08-18

·生物谷

《细胞》：橙子渣别扔，有大营养！肠菌大牛研究发现，橙子纤维中存在N-甲基-5羟色胺，或可增强肠道蠕动，改善肥胖

很多科普文都会劝告大家，即使是鲜榨果汁，也不是那么的健康，还是直接吃掉本体比较好，这样才不会错过很多膳食纤维。很多科普文都会劝告大家，即使是鲜榨果汁，也不是那么的健康，还是直接吃掉本体比较好，这样才不会错过很多膳食纤维。不过，榨汁过程中丢掉的包括果皮、种子和不可溶性膳食纤维等在内的“废料”中的有益物质含量可能超乎我们想象。最近，肠道微生物领域的大牛Jeffrey I Gordon教授的团队在《细胞》杂志上发表了一项新的研究成果[1]。他们发现，榨橙汁剩下的橙子纤维副产品中存在一种名为N-甲基-5羟色胺的有益物质，在小鼠中，它起到了增强肠道蠕动、改善肥胖、增加肝糖原生成，以及改变调节肝脏和结肠中昼夜节律基因表达的作用。研究人员还确定了一组特定的肠道微生物，只有它们能将N-甲基-5羟色胺从橙子纤维中“挖掘”出来。在人类中，也发现了橙子纤维与粪便N-甲基-5羟色胺的剂量依赖性关系。研究人员购买了食品级的榨汁副产物橙子纤维，这些橙子纤维只经过水洗、加热、脱水和剪切处理，没有使用化学制剂进行处理或提取。他们准备了四组成年无菌小鼠，其中两组定植了14种已进行过测序的人的肠道微生物，用同样的鼠粮喂养，其中一组包含10%的橙子纤维，另外两组也分别用同样的方式进行喂养，但保持无菌状态，持续21天。和另外三组相比，定植了菌群且饮食中含有橙子纤维的小鼠肠道中的物质含量至少增加了3倍，其中一种只在有菌有橙子纤维的小鼠中以高丰度存在，这种物质就是N-甲基-5羟色胺。N-甲基-5羟色胺此前在一些植物中被发现过，包括黑升麻、日本胡椒和柑橘类水果[2-4]。在133种不同的可食用植物产品（包括玉米、小麦和大米等主食，以及常见的果蔬）中，只有3种检测到了N-甲基-5羟色胺，它们都来自花椒属的花椒类产品，花椒属与柑橘属是亲戚，同属芸香科，而在各种类型的辣椒、甜椒（茄科）和普通黑胡椒（胡椒科）中都没有检测到。最后，他们在市售的23种橙子纤维中又进行了一波检测，虽然N-甲基-5羟色胺的含量有明显差别，但每种中都能检测到，含量的差别可能与橙子纤维的生产和处理方法有关。这表明，N-甲基-5羟色胺主要存在于柑橘类纤维中。 N-甲基-5羟色胺虽然是5-羟色胺的衍生物质，但是它对宿主的影响还没怎么被研究过。研究人员在两组无菌小鼠的饮用水中分别以1 mg/kg/天和50 mg/kg/天的剂量添加了N-甲基-5羟色胺，喝了21天之后，相比没有添加N-甲基-5羟色胺的对照组，两个干预组小鼠的体重增加显著减少，大剂量组还表现出附睾脂肪量的显著减少。不仅如此，大剂量组小鼠的肝糖原合成显著增加，其前体物质和代谢中间产物肝脏葡萄糖-6-磷酸水平均显著降低。与对照组相比，大剂量组小鼠肝脏中有716个基因表达存在显著差异，其中与昼夜节律和脂肪酸代谢有关的通路最为显著，Arntl和Clock表达降低，两者都与抑制糖异生和脂肪生成有关[5,6]，Per2，Per3和Nr1d2表达增加，Per2和Per3分别与促进糖原合成和抑制脂肪生成有关[7,8]，Nr1d2是Nfil3的抑制因子，Nfil3在肠道上皮细胞中的表达存在由肠道微生物调控的昼夜节律，伴随上皮脂质吸收和消化，Nfil3的缺失能够减轻高脂饮食小鼠的肥胖[9]。不仅是肝脏，小鼠结肠中也有748个基因表达存在显著差异，包括上述提到的昼夜节律基因，昼夜节律相关基因在肠道中的表达能够协调结肠蠕动[10]，因此，干预组小鼠的肠道运输时间相比对照组显著减少（p＜0.0001）。既然N-甲基-5羟色胺是一种来源于橙子纤维的有益物质，那我们就可以想办法用肠道微生物来“挖掘”它了。通过不同成分培养基的体外培养，研究人员确定了4种能够挖掘N-甲基-5羟色胺的肠道微生物，分别为卵形拟杆菌、迪氏副拟杆菌、芬氏拟杆菌和产气柯林斯氏菌。分别给三组无菌小鼠定植这4种菌的组合、完整的14种菌的组合和其余10种菌的组合后，4菌组小鼠的N-甲基-5羟色胺水平与14菌组小鼠相当，显著高于10菌组小鼠（p=0.002），体重增加和附睾脂肪量显著减少（p分别为0.007和0.001），肠道运输时间显著减少（p＜0.0001）。最后，为了证实他们的发现在人类中的可转化性，研究人员分析了为期10周的开放标签队列研究（密苏里州青少年女性双胞胎研究，MOAFTS）的参与者的粪便样本。队列中的参与者分为两组分别服用橙子纤维零食和豆类纤维零食（不含N-甲基-5羟色胺），从研究第3周开始每天吃一份，第四周增加到两份，第五周增加到三份，此时的摄入量约为25-30克/天，持续4周。橙子纤维组中98%的参与者粪便样本中都检测到了N-甲基-5羟色胺，且水平与每天的橙子纤维零食摄入量显著相关（r=0.72，p＜0.0001），而豆类纤维组中，即使是第五周摄入量最大的时候，仍有87%的参与者粪便样本中检测不到N-甲基-5羟色胺。研究人员还发现，第5周末时的N-甲基-5羟色胺水平与卵形拟杆菌或任何粪便菌群的相对丰度均无显著相关性，而是与碳水化合物活性酶（CAZyme）显著相关，正相关性最强的为PL9（鼠李半乳糖醛酸裂解酶），其次为β-葡聚糖/纤维素酶，其余有相关性的还包括具有同型半乳糖醛酸聚糖/鼠李半乳糖醛酸加工功能或靶向果胶成分的酶。也就是说，在人类中，摄入橙子纤维也能够产生N-甲基-5羟色胺，其水平与摄入量和肠道菌群消化果胶聚糖的酶的基因水平呈正相关。综上所述，Jeffrey I Gordon教授团队在本次的研究中为我们揭示了一种存在于橙子纤维中，可以被肠道微生物“挖掘”出来的有益物质，N-甲基-5羟色胺，具有潜在的减少肥胖和脂肪量、改善肠道蠕动，调节昼夜节律基因表达的作用。据Gordon教授介绍，2020年，全球生产了约1.4亿吨柑橘类水果，而工厂在生产果汁时，纤维副产物占到几乎一半重量，这些副产物如果能够在微生物的作用下得到二次利用，既有益于环境，也能够促进人类健康，而且不同的纤维具有不同的丰富的生物分子库，这其中的潜力是巨大的。