The Role of Nur77 in Glucose Metabolism Regulation: Implications for ARDS Pathophysiology

Authors

  • Li Jun MAHSA University, Jalan SP 2, Bandar Saujana Putra, 42610 Jenjarom, Selangor, Malaysia
  • Jiang Yujie Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
  • Chai Theam Ooi MAHSA University, Jalan SP 2, Bandar Saujana Putra, 42610 Jenjarom, Selangor, Malaysia
  • Barani Karikalan MAHSA University, Jalan SP 2, Bandar Saujana Putra, 42610 Jenjarom, Selangor, Malaysia

DOI:

https://doi.org/10.53797/fphj.v3i2.10.2024

Keywords:

Nur77, NR4A1, Glucose metabolism, Gene expression, acute respiratory distress syndrome

Abstract

Nur77 (Neuron-derived clone 77) is one of the members of the orphan nuclear receptor family, and its expression and activation are rapidly triggered under a variety of physiological and pathological stimuli and have complex biological activities. Studies indicate that Nur77 regulates glucose metabolism in a tissue-dependent manner, and this mechanism may play a role in the occurrence and progression of acute respiratory distress syndrome (ARDS). Understanding how Nur77 regulates glucose metabolism and how it influences the onset and progression of ARDS is expected to provide an opportunity to alter Nur77 to regulate glucose metabolism and explore novel targets for ARDS medication therapy. In this review, we will discuss the molecular biological functions and expression of Nur77, the regulation of glucose metabolism by Nur77, and its putative role in ARDS.

Author Biography

Li Jun, MAHSA University, Jalan SP 2, Bandar Saujana Putra, 42610 Jenjarom, Selangor, Malaysia

Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China

References

Acute respiratory distress syndrome in adults: Diagnosis, outcomes, long-term sequelae, and management—The lancet. (n.d.). Retrieved December 20, 2024, from https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01439-8/fulltext.

Ao, M., Zhang, J., Qian, Y., Li, B., Wang, X., Chen, J., Zhang, Y., Cao, Y., Qiu, Y., Xu, Y., Wu, Z., & Fang, M. (2022). Design and synthesis of adamantyl-substituted flavonoid derivatives as anti-inflammatory Nur77 modulators: Compound B7 targets Nur77 and improves LPS-induced inflammation in vitro and in vivo. Bioorganic Chemistry, 120, 105645. https://doi.org/10.1016/j.bioorg.2022.105645.

Ardid-Ruiz, A., Ibars, M., Mena, P., Del Rio, D., Muguerza, B., Bladé, C., Arola, L., Aragonès, G., & Suárez, M. (2018). Potential involvement of peripheral leptin/STAT3 signaling in the effects of resveratrol and its metabolites on reducing body fat accumulation. Nutrients, 10(11), 1757. https://doi.org/10.3390/nu10111757.

Banno, A., Lakshmi, S. P., Reddy, A. T., Kim, S. C., & Reddy, R. C. (2019a). Key functions and therapeutic prospects of Nur77 in inflammation related lung diseases. American Journal of Pathology, 189(3), 482–491. https://doi.org/10.1016/j.ajpath.2018.10.002.

Banno, A., Lakshmi, S. P., Reddy, A. T., Kim, S. C., & Reddy, R. C. (2019b). Key Functions and Therapeutic Prospects of Nur77 in Inflammation Related Lung Diseases. The American Journal of Pathology, 189(3), 482–491. https://doi.org/10.1016/j.ajpath.2018.10.002.

Bos, L. D. J., & Ware, L. B. (2022). Acute respiratory distress syndrome: Causes, pathophysiology, and phenotypes. The Lancet, 400(10358), 1145–1156. https://doi.org/10.1016/S0140-6736(22)01485-4.

Chao, L. C., Wroblewski, K., Ilkayeva, O. R., Stevens, R. D., Bain, J., Meyer, G. A., Schenk, S., Martinez, L., Vergnes, L., Narkar, V. A., Drew, B. G., Hong, C., Boyadjian, R., Hevener, A. L., Evans, R. M., Reue, K., Spencer, M. J., Newgard, C. B., & Tontonoz, P. (2012). Skeletal muscle Nur77 expression enhances oxidative metabolism and substrate utilization. Journal of Lipid Research, 53(12), 2610–2619. https://doi.org/10.1194/jlr.M029355.

Coulthard, L. R., White, D. E., Jones, D. L., McDermott, M. F., & Burchill, S. A. (2009). p38(MAPK): Stress responses from molecular mechanisms to therapeutics. Trends in Molecular Medicine, 15(8), 369–379. https://doi.org/10.1016/j.molmed.2009.06.005.

Deng, S., Chen, B., Huo, J., & Liu, X. (2022). Therapeutic potential of NR4A1 in cancer: Focus on metabolism. Frontiers in Oncology, 12, 972984. https://doi.org/10.3389/fonc.2022.972984.

Ding, R., Sun, X., Yi, B., Liu, W., Kazama, K., Xu, X., Deshpande, D. A., Liang, C., & Sun, J. (2021a). Nur77 attenuates inflammasome activation by inhibiting caspase-1 expression in pulmonary vascular endothelial cells. American Journal of Respiratory Cell and Molecular Biology, 65(3), 288–299. https://doi.org/10.1165/rcmb.2020-0524OC.

Ding, R., Sun, X., Yi, B., Liu, W., Kazama, K., Xu, X., Deshpande, D. A., Liang, C., & Sun, J. (2021b). Nur77 Attenuates Inflammasome Activation by Inhibiting Caspase-1 Expression in Pulmonary Vascular Endothelial Cells. American Journal of Respiratory Cell and Molecular Biology, 65(3), 288–299. https://doi.org/10.1165/rcmb.2020-0524OC.

Dolinay, T., Kaminski, N., Felgendreher, M., Kim, H. P., Reynolds, P., Watkins, S. C., Karp, D., Uhlig, S., & Choi, A. M. K. (2006). Gene expression profiling of target genes in ventilator-induced lung injury. Physiological Genomics, 26(1), 68–75. https://doi.org/10.1152/physiolgenomics.00110.2005.

Fang, H., Cao, Y., Zhang, J., Wang, X., Li, M., Hong, Z., Wu, Z., & Fang, M. (2023). Lipidome remodeling activities of DPA-EA in palmitic acid-stimulated HepG2 cells and the in vivo anti-obesity effect of the DPA-EA and DHA-EA mixture prepared from algae oil. Frontiers in Pharmacology, 14, 1146276. https://doi.org/10.3389/fphar.2023.1146276.

Fang, H., Li, M., Wang, X., Chen, W., He, F., Zhang, Y., Guo, K., Jin, W., Li, B., & Fang, M. (2023). Discovery of new DHA ethanolamine derivatives as potential anti-inflammatory agents targeting Nur77. Bioorganic Chemistry, 141, 106887. https://doi.org/10.1016/j.bioorg.2023.106887.

Fang, H., Zhang, J., Ao, M., He, F., Chen, W., Qian, Y., Zhang, Y., Xu, Y., & Fang, M. (2020). Synthesis and discovery of ω-3 polyunsaturated fatty acid- alkanolamine (PUFA-AA) derivatives as anti-inflammatory agents targeting Nur77. Bioorganic Chemistry, 105, 104456. https://doi.org/10.1016/j.bioorg.2020.104456.

Fassett, M. S., Jiang, W., D’Alise, A. M., Mathis, D., & Benoist, C. (2012). Nuclear receptor Nr4a1 modulates both regulatory T-cell (treg) differentiation and clonal deletion. Proceedings of the National Academy of Sciences of the United States of America, 109(10), 3891–3896. https://doi.org/10.1073/pnas.1200090109.

Herring, J. A., Crabtree, J. E., Hill, J. T., & Tessem, J. S. (2024). Loss of glucose-stimulated β-cell Nr4a1 expression impairs insulin secretion and glucose homeostasis. American Journal of Physiology. Cell Physiology, 327(4), C1111–C1124. https://doi.org/10.1152/ajpcell.00315.2024.

Hwang, S.-L., Kwon, O., Lee, S. J., Roh, S.-S., Kim, Y. D., & Choi, J. H. (2012). B-cell translocation gene-2 increases hepatic gluconeogenesis via induction of CREB. Biochemical and Biophysical Research Communications, 427(4), 801–805. https://doi.org/10.1016/j.bbrc.2012.09.146.

Jiang, Y., Zeng, Y., Huang, X., Qin, Y., Luo, W., Xiang, S., Sooranna, S. R., & Pinhu, L. (2016a). Nur77 attenuates endothelin-1 expression via downregulation of NF-κB and p38 MAPK in A549 cells and in an ARDS rat model. American Journal of Physiology Lung Cellular and Molecular Physiology, 311(6), L1023–L1035. https://doi.org/10.1152/ajplung.00043.2016.

Jiang, Y., Zeng, Y., Huang, X., Qin, Y., Luo, W., Xiang, S., Sooranna, S. R., & Pinhu, L. (2016b). Nur77 attenuates endothelin-1 expression via downregulation of NF-κB and p38 MAPK in A549 cells and in an ARDS rat model. American Journal of Physiology. Lung Cellular and Molecular Physiology, 311(6), L1023–L1035. https://doi.org/10.1152/ajplung.00043.2016.

Kanzleiter, T., Preston, E., Wilks, D., Ho, B., Benrick, A., Reznick, J., Heilbronn, L. K., Turner, N., & Cooney, G. J. (2010). Overexpression of the orphan receptor Nur77 alters glucose metabolism in rat muscle cells and rat muscle in vivo. Diabetologia, 53(6), 1174–1183. https://doi.org/10.1007/s00125-010-1703-2.

Kanzleiter, T., Wilks, D., Preston, E., Ye, J., Frangioudakis, G., & Cooney, G. J. (2009). Regulation of the nuclear hormone receptor nur77 in muscle: Influence of exercise-activated pathways in vitro and obesity in vivo. Biochimica et Biophysica Acta, 1792(8), 777–782. https://doi.org/10.1016/j.bbadis.2009.05.002.

Kim, Y. D., Kim, S.-G., Hwang, S.-L., Choi, H.-S., Bae, J.-H., Song, D.-K., & Im, S.-S. (2014). B-cell translocation gene 2 regulates hepatic glucose homeostasis via induction of orphan nuclear receptor Nur77 in diabetic mouse model. Diabetes, 63(6), 1870–1880. https://doi.org/10.2337/db13-1368.

Kovalovsky, D., Refojo, D., Liberman, A. C., Hochbaum, D., Pereda, M. P., Coso, O. A., Stalla, G. K., Holsboer, F., & Arzt, E. (2002). Activation and induction of NUR77/NURR1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase a, and MAPK pathways. Molecular Endocrinology (Baltimore, Md.), 16(7), 1638–1651. https://doi.org/10.1210/mend.16.7.0863.

Kurakula, K., Koenis, D. S., van Tiel, C. M., & de Vries, C. J. M. (2014). NR4A nuclear receptors are orphans but not lonesome. Biochimica et Biophysica Acta, 1843(11), 2543–2555. https://doi.org/10.1016/j.bbamcr.2014.06.010.

Li, Y., Wang, S.-M., Li, X., Lv, C.-J., Peng, L.-Y., Yu, X.-F., Song, Y.-J., & Wang, C.-J. (2022). Pterostilbene pre-treatment reduces LPS-induced acute lung injury through activating NR4A1. Pharmaceutical Biology, 60(1), 394–403. https://doi.org/10.1080/13880209.2022.2034893.

Liebmann, M., Hucke, S., Koch, K., Eschborn, M., Ghelman, J., Chasan, A. I., Glander, S., Schädlich, M., Kuhlencord, M., Daber, N. M., Eveslage, M., Beyer, M., Dietrich, M., Albrecht, P., Stoll, M., Busch, K. B., Wiendl, H., Roth, J., Kuhlmann, T., & Klotz, L. (2018). Nur77 serves as a molecular brake of the metabolic switch during T cell activation to restrict autoimmunity. Proceedings of the National Academy of Sciences of the United States of America, 115(34), E8017–E8026. https://doi.org/10.1073/pnas.1721049115.

Lopes-Pacheco, M., Robba, C., Rocco, P. R. M., & Pelosi, P. (2020). Current understanding of the therapeutic benefits of mesenchymal stem cells in acute respiratory distress syndrome. Cell Biology and Toxicology, 36(1), 83–102. https://doi.org/10.1007/s10565-019-09493-5.

Mahoney, D. J., Parise, G., Melov, S., Safdar, A., & Tarnopolsky, M. A. (2005). Analysis of global mRNA expression in human skeletal muscle during recovery from endurance exercise. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 19(11), 1498–1500. https://doi.org/10.1096/fj.04-3149fje.

Maxwell, M. A., Cleasby, M. E., Harding, A., Stark, A., Cooney, G. J., & Muscat, G. E. O. (2005a). Nur77 regulates lipolysis in skeletal muscle cells. Evidence for cross-talk between the beta-adrenergic and an orphan nuclear hormone receptor pathway. Journal of Biological Chemistry, 280(13), 12573–12584. https://doi.org/10.1074/jbc.M409580200.

Maxwell, M. A., Cleasby, M. E., Harding, A., Stark, A., Cooney, G. J., & Muscat, G. E. O. (2005b). Nur77 regulates lipolysis in skeletal muscle cells: EVIDENCE FOR CROSS-TALK BETWEEN THE β-ADRENERGIC AND AN ORPHAN NUCLEAR HORMONE RECEPTOR PATHWAY*. Journal of Biological Chemistry, 280(13), 12573–12584. https://doi.org/10.1074/jbc.M409580200.

Maxwell, M. A., & Muscat, G. E. O. (2006). The NR4A subgroup: Immediate early response genes with pleiotropic physiological roles. Nuclear Receptor Signaling, 4, e002. https://doi.org/10.1621/nrs.04002.

Mey, J. T., Solomon, T. P. J., Kirwan, J. P., & Haus, J. M. (2019a). Skeletal muscle Nur77 and NOR1 insulin responsiveness is blunted in obesity and type 2 diabetes but improved after exercise training. Physiological Reports, 7(6), e14042. https://doi.org/10.14814/phy2.14042.

Mey, J. T., Solomon, T. P. J., Kirwan, J. P., & Haus, J. M. (2019b). Skeletal muscle Nur77 and NOR1 insulin responsiveness is blunted in obesity and type 2 diabetes but improved after exercise training. Physiological Reports, 7(6), e14042. https://doi.org/10.14814/phy2.14042.

Miao, L., Yang, Y., Liu, Y., Lai, L., Wang, L., Zhan, Y., Yin, R., Yu, M., Li, C., Yang, X., & Ge, C. (2019). Glycerol kinase interacts with nuclear receptor NR4A1 and regulates glucose metabolism in the liver. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 33(6), 6736–6747. https://doi.org/10.1096/fj.201800945RR.

Ming, Y., Yin, Y., & Sun, Z. (2020). Interaction of nuclear receptor subfamily 4 group a member 1 (Nr4a1) and liver linase B1 (LKB1) mitigates type 2 diabetes mellitus by activating monophosphate-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) axis and inhibiting nuclear factor-kappa B (NF-κB) activation. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 26, e920278. https://doi.org/10.12659/MSM.920278.

Mohankumar, K., Lee, J., Wu, C. S., Sun, Y., & Safe, S. (2018). Bis-indole-derived NR4A1 ligands and metformin exhibit NR4A1-dependent glucose metabolism and uptake in C2C12 cells. Endocrinology, 159(5), 1950–1963. https://doi.org/10.1210/en.2017-03049.

Oita, R. C., Mazzatti, D. J., Lim, F. L., Powell, J. R., & Merry, B. J. (2009). Whole-genome microarray analysis identifies up-regulation of Nr4a nuclear receptors in muscle and liver from diet-restricted rats. Mechanisms of Ageing and Development, 130(4), 240–247. https://doi.org/10.1016/j.mad.2008.12.004.

Pearen, M. A., & Muscat, G. E. O. (2010). Minireview: Nuclear hormone receptor 4A signaling: Implications for metabolic disease. Molecular Endocrinology (Baltimore, Md.), 24(10), 1891–1903. https://doi.org/10.1210/me.2010-0015.

Pearen, M. A., Ryall, J. G., Maxwell, M. A., Ohkura, N., Lynch, G. S., & Muscat, G. E. O. (2006). The orphan nuclear receptor, NOR-1, is a target of beta-adrenergic signaling in skeletal muscle. Endocrinology, 147(11), 5217–5227. https://doi.org/10.1210/en.2006-0447.

Pei, L., Waki, H., Vaitheesvaran, B., Wilpitz, D. C., Kurland, I. J., & Tontonoz, P. (2006). NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism. Nature Medicine, 12(9), 1048–1055. https://doi.org/10.1038/nm1471.

Petersen, K. F., & Shulman, G. I. (2006). Etiology of insulin resistance. American Journal of Medicine, 119(5 Suppl 1), S10-16. https://doi.org/10.1016/j.amjmed.2006.01.009.

Praslicka, B., Harmson, J. S., Kim, J., Rangaraj, V. R., Ooi, A., & Gissendanner, C. R. (2017). Binding site analysis of the caenorhabditis elegans nr4a nuclear receptor nhr-6 during development. Nuclear Receptor Research, 4, 101288. https://doi.org/10.11131/2017/101288.

Reynolds, M. S., Hancock, C. R., Ray, J. D., Kener, K. B., Draney, C., Garland, K., Hardman, J., Bikman, B. T., & Tessem, J. S. (2016). β-cell deletion of Nr4a1 and Nr4a3 nuclear receptors impedes mitochondrial respiration and insulin secretion. American Journal of Physiology. Endocrinology and Metabolism, 311(1), E186-201. https://doi.org/10.1152/ajpendo.00022.2016.

Sasaki, S., Nian, C., Xu, E. E., Pasula, D. J., Winata, H., Grover, S., Luciani, D. S., & Lynn, F. C. (2023). Type 2 diabetes susceptibility gene GRK5 regulates physiological pancreatic β-cell proliferation via phosphorylation of HDAC5. iScience, 26(8), 107311. https://doi.org/10.1016/j.isci.2023.107311.

Saucedo-Cardenas, O., Kardon, R., Ediger, T. R., Lydon, J. P., & Conneely, O. M. (1997). Cloning and structural organization of the gene encoding the murine nuclear receptor transcription factor, NURR1. Gene, 187(1), 135–139. https://doi.org/10.1016/s0378-1119(96)00736-6.

Sommer, N., Pak, O., & Hecker, M. (2021). New Avenues for Antiinflammatory Signaling of Nur77 in Acute Lung Injury. American Journal of Respiratory Cell and Molecular Biology, 65(3), 236–237. https://doi.org/10.1165/rcmb.2021-0210ED.

Sunil, V. R., Vayas, K. N., Radbel, J., Abramova, E., Gow, A., Laskin, J. D., & Laskin, D. L. (2022). Impaired energy metabolism and altered functional activity of alveolar type II epithelial cells following exposure of rats to nitrogen mustard. Toxicology and Applied Pharmacology, 456, 116257. https://doi.org/10.1016/j.taap.2022.116257.

Tontonoz, P., Cortez-Toledo, O., Wroblewski, K., Hong, C., Lim, L., Carranza, R., Conneely, O., Metzger, D., & Chao, L. C. (2015). The orphan nuclear receptor Nur77 is a determinant of myofiber size and muscle mass in mice. Molecular and Cellular Biology, 35(7), 1125–1138. https://doi.org/10.1128/MCB.00715-14.

Wang, Y., Thaler, M., Salgado-Benvindo, C., Ly, N., Leijs, A. A., Ninaber, D. K., Hansbro, P. M., Boedijono, F., van Hemert, M. J., Hiemstra, P. S., van der Does, A. M., & Faiz, A. (2024). SARS-CoV-2-infected human airway epithelial cell cultures uniquely lack interferon and immediate early gene responses caused by other coronaviruses. Clinical & Translational Immunology, 13(4), e1503. https://doi.org/10.1002/cti2.1503.

Xie, P., Yan, L.-J., Zhou, H.-L., Cao, H.-H., Zheng, Y.-R., Lu, Z.-B., Yang, H.-Y., Ma, J.-M., Chen, Y.-Y., Huo, C., Tian, C., Liu, J.-S., & Yu, L.-Z. (2022). Emodin Protects Against Lipopolysaccharide-Induced Acute Lung Injury via the JNK/Nur77/c-Jun Signaling Pathway. Frontiers in Pharmacology, 13, 717271. https://doi.org/10.3389/fphar.2022.717271.

Xu, Y., Tian, J., Kang, Q., Yuan, H., Liu, C., Li, Z., Liu, J., & Li, M. (2022). Knockout of Nur77 leads to amino acid, lipid, and glucose metabolism disorders in zebrafish. Frontiers in Endocrinology, 13, 864631. https://doi.org/10.3389/fendo.2022.864631.

Yu, C., Cui, S., Zong, C., Gao, W., Xu, T., Gao, P., Chen, J., Qin, D., Guan, Q., Liu, Y., Fu, Y., Li, X., & Wang, X. (2015). The orphan nuclear receptor NR4A1 protects pancreatic β-cells from endoplasmic reticulum (ER) stress-mediated apoptosis. Journal of Biological Chemistry, 290(34), 20687–20699. https://doi.org/10.1074/jbc.M115.654863.

Zhan, Y., Chen, Y., Zhang, Q., Zhuang, J., Tian, M., Chen, H., Zhang, L., Zhang, H., He, J., Wang, W., Wu, R., Wang, Y., Shi, C., Yang, K., Li, A., Xin, Y., Li, T. Y., Yang, J. Y., Zheng, Z., … Wu, Q. (2012). The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK. Nature Chemical Biology, 8(11), 897–904. https://doi.org/10.1038/nchembio.1069.

Zhou, F., Bai, M., Zhang, Y., Zhu, Q., Zhang, L., Zhang, Q., Wang, S., Zhu, K., Liu, Y., Wang, X., & Zhou, L. (2018). Berberine-induced activation of AMPK increases hepatic FGF21 expression via NUR77. Biochemical and Biophysical Research Communications, 495(2), 1936–1941. https://doi.org/10.1016/j.bbrc.2017.12.070.

Zhou, H., Yang, T., Lu, Z., He, X., Quan, J., Liu, S., Chen, Y., Wu, K., Cao, H., Liu, J., & Yu, L. (2023). Liquiritin exhibits anti-acute lung injury activities through suppressing the JNK/Nur77/c-Jun pathway. Chinese Medicine, 18(1), 35. https://doi.org/10.1186/s13020-023-00739-3.

Zhu, N., Zhang, G.-X., Yi, B., Guo, Z.-F., Jang, S., Yin, Y., Yang, F., Summer, R., & Sun, J. (2019). Nur77 limits endothelial barrier disruption to LPS in the mouse lung. American Journal of Physiology. Lung Cellular and Molecular Physiology, 317(5), L615–L624. https://doi.org/10.1152/ajplung.00425.2018.

Zhu, P., Wang, J., Du, W., Ren, J., Zhang, Y., Xie, F., & Xu, G. (2022). NR4A1 Promotes LPS-Induced Acute Lung Injury through Inhibition of Opa1-Mediated Mitochondrial Fusion and Activation of PGAM5-Related Necroptosis. Oxidative Medicine and Cellular Longevity, 2022, 6638244. https://doi.org/10.1155/2022/6638244.

Downloads

Published

2024-12-26

How to Cite

Jun, L., Yujie, J. ., Chai, T. O., & Karikalan, B. . (2024). The Role of Nur77 in Glucose Metabolism Regulation: Implications for ARDS Pathophysiology. Fitness, Performance and Health Journal, 3(2), 128–141. https://doi.org/10.53797/fphj.v3i2.10.2024