NR4A1在肥胖相关炎症反应中的研究进展
Research Progress of NR4A1 in Obesity-Related Inflammatory Response
DOI: 10.12677/ACM.2023.1361286, PDF,   
作者: 信立霞, 何天阳：大连医科大学研究生院，辽宁 大连；张玉超, 左 丹, 王延淼：青岛市市立医院内分泌科，山东 青岛；刘元涛*：山东大学齐鲁医院(青岛)内分泌科，山东 青岛
关键词: NR4A1；肥胖；炎症反应；NLRP3炎症小体信号通路；细胞焦亡；NR4A1； Obesity； Inflammatory Response； NLRP3 Inflammasome Signaling Pathway； Pyroptosis
摘要: 孤核受体NR4A1作为转录调节因子，它可识别特异性受体并在转录水平调控线粒体自噬和细胞凋亡等生物学过程的基因表达，在物质代谢、能量平衡、炎症反应等机体活动中发挥重要作用。肥胖是导致胰岛素抵抗和2型糖尿病等代谢性疾病的重要危险因素，它的主要特征是脂肪组织低度慢性炎症和巨噬细胞浸润。肥胖的发展过程中，营养过剩产生的危险分子信号会激活核苷酸结合寡聚化结构域样受体蛋白3 (nucleotide-binding oligomerization domain-like receptor protein 3, NLRP3)炎症小体信号通路，导致炎症反应和细胞焦亡。本文旨在阐述肥胖与炎症反应的联系、NR4A1在炎症反应中的应用，为治疗肥胖及预防相关炎症性疾病提供新的思路。
Abstract: As a transcriptional regulator, orphan nuclear receptor NR4A1 can identify specific receptors and regulate gene expression in biological processes such as mitochondrial autophagy and apoptosis at the transcriptional level, and play an important role in body activities such as material metabolism, energy balance and inflammation. Obesity is an important risk factor for metabolic diseases such as insulin resistance and type 2 diabetes. It is characterized by low-grade chronic inflammation of ad-ipose tissue and macrophage infiltration. In the development of obesity, the risk molecular signal produced by over nutrition will activate the NLRP3 (nucleotide-binding oligomerization do-main-like receptor protein 3) inflammatory body signal pathway, leading to inflammatory response and pyroptosis. The purpose of this article is to explain the relationship between obesity and in-flammation and the application of NR4A1 in inflammation, and to provide new ideas for the treat-ment of obesity and prevention of related inflammatory diseases.
文章引用：信立霞, 何天阳, 张玉超, 左丹, 王延淼, 刘元涛. NR4A1在肥胖相关炎症反应中的研究进展[J]. 临床医学进展, 2023, 13(6): 9182-9187. https://doi.org/10.12677/ACM.2023.1361286

参考文献

[1] Selassie, M. and Sinha, A.C. (2011) The Epidemiology and Aetiology of Obesity: A Global Challenge. Best Practice & Research Clinical Anaesthesiology, 25, 1-9. [Google Scholar] [CrossRef] [PubMed]
[2] 曲伸, 陆灏, 宋勇峰. 基于临床的肥胖症多学科诊疗共识(2021年版) [J]. 中华肥胖与代谢病电子杂志, 2021, 7(4): 211-226.
[3] Karczewski, J., Śledzińska, E., Baturo, A., et al. (2018) Obesity and Inflammation. European Cytokine Network, 29, 83-94. [Google Scholar] [CrossRef] [PubMed]
[4] 袁亚慧, 袁蓉, 信琪琪, 等. NR4A1在动脉粥样硬化炎症和病理性血管新生中作用的研究进展[J]. 中西医结合心脑血管病杂志, 2022, 20(8): 1409-1412.
[5] Mangelsdorf, D.J., Thummel, C., Beato, M., et al. (1995) The Nuclear Receptor Superfamily: The Second Decade. Cell, 83, 835-839. [Google Scholar] [CrossRef] 
[6] 吴凌娟, 徐晓丽, 林峻, 等. 核受体参与调控细胞自噬的研究进展[J]. 生物医学工程学杂志, 2018, 35(5): 822-828.
[7] Wu, L. and Chen, L. (2018) Characteristics of Nur77 and Its Ligands as Potential Anticancer Compounds (Review). Molecular Medicine Reports, 18, 4793-4801. [Google Scholar] [CrossRef] [PubMed]
[8] 谷亚龙, 张新东, 金保方. 核受体NR4A1功能及调控的研究进展[J]. 中华临床医师杂志(电子版), 2014, 8(8): 1507-1511.
[9] Nuclear Receptor 4A (NR4A) Family-Orphans No More.
[10] Kurakula, K., Koenis, D.S., van Tiel, C.M., et al. (2014) NR4A Nuclear Receptors Are Orphans but Not Lonesome. Biochimica et Biophysica Acta (BBA)—Molecular Cell Research, 1843, 2543-2555. [Google Scholar] [CrossRef] [PubMed]
[11] Zhang, L., Wang, Q., Liu, W., et al. (2018) The Orphan Nuclear Receptor 4A1: A Potential New Therapeutic Target for Metabolic Diseases. Journal of Diabetes Research, 2018, Article ID: 9363461. [Google Scholar] [CrossRef] [PubMed]
[12] Rodríguez-Calvo, R., Tajes, M. and Vázquez-Carrera, M. (2017) The NR4A Subfamily of Nuclear Receptors: Potential New Therapeutic Targets for the Treatment of Inflammatory Diseases. Expert Opinion on Therapeutic Targets, 21, 291-304. [Google Scholar] [CrossRef] [PubMed]
[13] Hanna, R.N., Shaked, I., Hubbeling, H.G., et al. (2012) NR4A1 (Nur77) Deletion Polarizes Macrophages toward an Inflamma-tory Phenotype and Increases Atherosclerosis. Circulation Research, 110, 416-427. [Google Scholar] [CrossRef] 
[14] You, B., Jiang, Y.-Y., Chen, S.P., et al. (2009) The Or-phan Nuclear Receptor Nur77 Suppresses Endothelial Cell Activation through Induction of IκBα Expression. Circulation Research, 104, 742-749. [Google Scholar] [CrossRef] 
[15] Hu, M.J., Luo, Q., Alitongbieke, G., et al. (2017) Celas-trol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy. Molecular Cell, 66, 141-153.e6. [Google Scholar] [CrossRef] [PubMed]
[16] Koenis, D.S., Medzikovic, L., van Loenen, P.B., et al. (2018) Nuclear Receptor Nur77 Limits the Macrophage Inflammatory Response through Transcriptional Reprogramming of Mitochondrial Metabolism. Cell Reports, 24, 2127- 2140.e7. [Google Scholar] [CrossRef] [PubMed]
[17] Bonta, P.I., van Tiel, C.M., Vos, M., et al. (2006) Nuclear Re-ceptors Nur77, Nurr1, and NOR-1 Expressed in Atherosclerotic Lesion Macrophages Reduce Lipid Loading and In-flammatory Responses. Arteriosclerosis, Thrombosis, and Vascular Biology, 26, 2288-2288. [Google Scholar] [CrossRef] 
[18] Shaked, I., Hanna, R.N., Shaked, H., et al. (2015) Transcription Factor Nr4a1 Couples Sympathetic and Inflammatory Cues in CNS-Recruited Macrophages to Limit Neu-roinflammation. Nature Immunology, 16, 1228-1234. [Google Scholar] [CrossRef] [PubMed]
[19] Li, L., Liu, Y., Chen, H., et al. (2015) Impeding the Interaction between Nur77 and p38 Reduces LPS-Induced Inflammation. Nature Chemical Biology, 11, 339-346. [Google Scholar] [CrossRef] [PubMed]
[20] Hu, M., Luo, Q., Alitongbieke, G., et al. (2017) Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy. Molecular Cell, 66, 141-153.e6. [Google Scholar] [CrossRef] [PubMed]
[21] Shao, Q., Shen, L.-H., Hu, L.-H., et al. (2010) Nuclear Receptor Nur77 Suppresses Inflammatory Response Dependent on COX-2 in Macrophages Induced by oxLDL. Journal of Mo-lecular and Cellular Cardiology, 49, 304-311. [Google Scholar] [CrossRef] [PubMed]
[22] Pei, L.M., Castrillo, A. and Tontonoz, P. (2006) Regulation of Macrophage Inflammatory Gene Expression by the Orphan Nuclear Receptor Nur77. Molecular Endocrinology, 20, 786-794. [Google Scholar] [CrossRef] [PubMed]
[23] Holmes, W.F., Soprano, D.R. and Soprano, K.J. (2003) Early Events in the Induction of Apoptosis in Ovarian Carcinoma Cells by CD437: Activation of the p38 MAP Kinase Signal Pathway. Oncogene, 22, 6377-6386. [Google Scholar] [CrossRef] [PubMed]
[24] Zhao, Y., Liu, Y. and Zheng, D. (2008) Alpha 1-Antichymotrypsin/SerpinA3 Is a Novel Target of Orphan Nuclear Receptor Nur77: SerpinA3 Is a Novel Target of Nur77. FEBS Journal, 275, 1025-1038. [Google Scholar] [CrossRef] [PubMed]
[25] Pei, L., Castrillo, A., Chen, M., et al. (2005) Induction of NR4A Orphan Nuclear Receptor Expression in Macrophages in Response to Inflammatory Stimuli. Journal of Biological Chemistry, 280, 29256-29262. [Google Scholar] [CrossRef] 
[26] Hotamisligil, G.S. (2006) Inflammation and Metabolic Disorders. Nature, 444, 860-867. [Google Scholar] [CrossRef] [PubMed]
[27] Lumeng, C.N. and Saltiel, A.R. (2011) Inflammatory Links between Obesity and Metabolic Disease. Journal of Clinical Investigation, 121, 2111-2117. [Google Scholar] [CrossRef] 
[28] Takeuchi, O. and Akira, S. (2010) Pattern Recognition Receptors and In-flammation. Cell, 140, 805-820. [Google Scholar] [CrossRef] [PubMed]
[29] Wen, H.T., Gris, D., Lei, Y., et al. (2011) Fatty Acid-Induced NLRP3-ASC Inflammasome Activation Interferes with Insulin Signaling. Nature Immunology, 12, 408-415. [Google Scholar] [CrossRef] [PubMed]
[30] Schroder, K. and Tschopp, J. (2010) The Inflammasomes. Cell, 140, 821-832. [Google Scholar] [CrossRef] [PubMed]
[31] Jo, E.-K., Kim, J.K., Shin, D.-M., et al. (2016) Molecular Mecha-nisms Regulating NLRP3 Inflammasome Activation. Cellular & Molecular Immunology, 13, 148-159. [Google Scholar] [CrossRef] [PubMed]
[32] Chen, S.Z. and Sun, B. (2013) Negative Regulation of NLRP3 Inflam-masome Signaling. Protein & Cell, 4, 251-258. [Google Scholar] [CrossRef] [PubMed]
[33] Vandanmagsar, B., Youm, Y.-H., Ravussin, A., et al. (2011) The NLRP3 Inflammasome Instigates Obesity-Induced Inflammation and Insulin Resistance. Nature Medicine, 17, 179-188. [Google Scholar] [CrossRef] [PubMed]
[34] Stienstra, R., van Diepen, J.A., Tack, C.J., et al. (2011) Inflammasome Is a Central Player in the Induction of Obesity and Insulin Resistance. Proceedings of the National Academy of Sciences, 108, 15324-15329. [Google Scholar] [CrossRef] [PubMed]
[35] Bergsbaken, T., Fink, S.L. and Cookson, B.T. (2009) Pyroptosis: Host Cell Death and Inflammation. Nature Reviews Microbiology, 7, 99-109. [Google Scholar] [CrossRef] [PubMed]
[36] Shi, J.J., Gao, W.Q. and Shao, F. (2017) Pyroptosis: Gasder-min-Mediated Programmed Necrotic Cell Death. Trends in Biochemical Sciences, 42, 245-254. [Google Scholar] [CrossRef] [PubMed]
[37] Cani, P.D., Bibiloni, R., Knauf, C., et al. (2008) Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet-Induced Obesity and Diabetes in Mice. Diabetes, 57, 1470-1481. [Google Scholar] [CrossRef] [PubMed]
[38] Giordano, A., Murano, I., Mondini, E., et al. (2013) Obese Adipocytes Show Ultrastructural Features of Stressed Cells and Die of Pyroptosis. Journal of Lipid Research, 54, 2423-2436. [Google Scholar] [CrossRef] 
[39] Sehgal, A., Behl, T., Kaur, I., et al. (2021) Targeting NLRP3 Inflam-masome as a Chief Instigator of Obesity, Contributing to Local Adipose Tissue Inflammation and Insulin Resistance. En-vironmental Science and Pollution Research, 28, 43102-43113. [Google Scholar] [CrossRef] [PubMed]
[40] 吴旭婷. NR4A1在2型糖尿病脂毒性诱导的胰岛β细胞焦亡中的作用研究[D]: [硕士学位论文]. 济南: 山东大学, 2022.

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