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血小板衍生生长因子及受体在肥胖和糖尿病中的研究进展
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Abstract:
近年来肥胖和糖尿病的患病率逐年增加，严重影响人们的生活质量。随着科研的不断进展，这类疾病的相关分子及信号通路的研究成为热门。血小板衍生生长因子(platelet-derived growth factor, PDGF)作为一种促血管生成因子，成员有PDGF-AA，PDGF-BB，PDGF-CC，PDGF-DD，PDGF-AB五种类型，其受体(platelet-derived growth factor receptor, PDGFR)属于酪氨酸蛋白激酶受体家族，它们不仅参与血管再生和创伤修复等重要生理过程，还在肿瘤细胞增殖、迁移及器官组织纤维化方面发挥重要作用，PDGF/PDGFR已成为基础生物学与转化医学研究所关注的重要靶点。近年研究发现，PDGF配体及受体与脂肪组织扩增及糖代谢关系密切。本文总结了目前已知关于PDGF及受体的结构与功能，并对其在肥胖及糖尿病方面的研究进行了梳理，以期望其能为肥胖和糖尿病的研究和治疗提供新方向。
In recent years, the prevalence of obesity and diabetes is increasing gradually, which seriously af-fects the quality of people’s life severely. With the advance of scientific research, the related mole-cules and signaling pathways of these diseases have become a hot topic. Platelet-derived growth factor (PDGF), as an angiogenic cytokines, consists of five molecular structures including PDGF-AA, PDGF-BB, PDGF-CC, PDGF-DD and PDGF-AB. Platelet-derived growth factor receptor (PDGFR) belongs to the tyrosine protein kinase receptor family. Platelet-derived growth factor receptor is not only involved in important physiological processes such as angiogenesis and wound repair, but also plays an important role in tumor cell proliferation, migration and organ tissue fibrosis. PDGF/PDGFR has become an important target in the research of basic biology and translational medicine. In recent years, it has been found that PDGFs and their receptors are closely related to adipose expansion and glucose metabolism. In this paper, the structure and function of PDGF and its receptors were summarized, and the research on its role in obesity and diabetes was reviewed in order to provide a new direction for the research and treatment of obesity and diabetes.
| [1] | 中国居民营养与慢性病状况报告(2020年) [J]. 营养学报, 2020, 42(6): 521. |
| [2] | Li, Y., Teng, D., Shi, X., et al. (2020) Prevalence of Diabetes Recorded in Mainland China Using 2018 Diagnostic Criteria from the American Diabetes Association: National Cross Sectional Study. BMJ, 369, Article No. m997.
https://doi.org/10.1136/bmj.m997 |
| [3] | 中华医学会糖尿病学分会. 中国2型糖尿病防治指南(2020年版) [J]. 国际内分泌代谢杂志, 2021, 41(5): 482-548. |
| [4] | Heilbronn, L.K., Noakes, M. and Clifton, P.M. (1999) Effect of Energy Restriction, Weight Loss, and Diet Composition on Plasma Lipids and Glucose in Patients with Type 2 Diabetes. Diabetes Care, 22, 889-895.
https://doi.org/10.2337/diacare.22.6.889 |
| [5] | Saltiel, A.R. and Olefsky, J.M. (2017) Inflammatory Mechanisms Linking Obesity and Metabolic Disease. Journal of Clinical Investigation, 127, 1-4. https://doi.org/10.1172/JCI92035 |
| [6] | Montgomery, M.K., De Nardo, W. and Watt, M.J. (2019) Impact of Lipo-toxicity on Tissue “Cross Talk” and Metabolic Regulation. Physiology, 34, 134-149. https://doi.org/10.1152/physiol.00037.2018 |
| [7] | Marmugi, A., Parnis, J., Chen, X., et al. (2016) Sorcin Links Pancreatic β-Cell Lipotoxicity to ER Ca2+ Stores. Diabetes, 65, 1009-1021. https://doi.org/10.2337/db15-1334 |
| [8] | Kumari, R., Kumar, S. and Kant, R. (2019) An Update on Metabolic Syn-drome: Metabolic Risk Markers and Adipokines in the Development of Metabolic Syndrome. Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 13, 2409-2417. https://doi.org/10.1016/j.dsx.2019.06.005 |
| [9] | Kaplan, D.R., Chao, F.C., Stiles, C.D., et al. (1979) Platelet Alpha Granules Contain a Growth Factor for Fibroblasts. Blood, 53, 1043-1052. https://doi.org/10.1182/blood.V53.6.1043.bloodjournal5361043 |
| [10] | Corsinovi, D., Giannetti, K., Ce-ricola, A., Naef, V. and Ori, M. (2019) PDGF-B: The Missing Piece in the Mosaic of PDGF Family Role in Craniofacial Development. Developmental Dynamics, 248, 603-612.
https://doi.org/10.1002/dvdy.47 |
| [11] | Li, X., Pontén, A., Aase, K., et al. (2000) PDGF-C Is a New Prote-ase-Activated Ligand for the PDGF α-Receptor. Nature Cell Biology, 2, 302-309. https://doi.org/10.1038/35010579 |
| [12] | Junkunlo, K., S？derh？ll, K., Noonin, C. and S？derh？ll, I. (2017) PDGF/VEGF-Related Receptor Affects Transglutaminase Activity to Control Cell Migration during Crustacean Hema-topoiesis. Stem Cells and Development, 26, 1449-1459. https://doi.org/10.1089/scd.2017.0086 |
| [13] | Klinkhammer, B.M., Floege, J. and Boor, P. (2018) PDGF in Organ Fibrosis. Molecular Aspects of Medicine, 62, 44-62. https://doi.org/10.1016/j.mam.2017.11.008 |
| [14] | Fredriksson, L., Li, H. and Eriksson, U. (2004) The PDGF Family: Four Gene Products Form Five Dimeric Isoforms. Cytokine & Growth Factor Reviews, 15, 197-204. https://doi.org/10.1016/j.cytogfr.2004.03.007 |
| [15] | Kazlauskas, A. (2017) PDGFs and Their Receptors. Gene, 614, 1-7. https://doi.org/10.1016/j.gene.2017.03.003 |
| [16] | 王媚媚, 秦晓红, 米立志. 血小板衍生生长因子受体结构与功能的研究[J]. 中国科学(生命科学), 2019, 49(6): 683-697. |
| [17] | Miller-Kasprzak, E., Niemir, Z.I. and Czekalski, S. (2004) The Role of Platelet-Derived Growth Factor A (PDGF-A) in Hypertension and Renal Diseases. Part 1: Struc-ture and Regulation of the PDGF-A Gene Expression and Its Role in Hypertension. Polski Merkuriusz Lekarski, 16, 398-401. (In Polish) |
| [18] | Wu, W.-B., Chiang, H.-S., Fang, J.-Y. and Hung, C.-F. (2007) Inhibitory Effect of Lycopene on PDGF-BB-Induced Signalling and Migration in Human Dermal Fibroblasts: A Possible Target for Cancer. Biochem-ical Society Transactions, 35, 1377-1378. https://doi.org/10.1042/BST0351377 |
| [19] | Lee, C., Zhang, F., Tang, Z., Liu, Y. and Li, X. (2013) PDGF-C: A New Performer in the Neurovascular Interplay. Trends in Molecular Medicine, 19, 474-486. https://doi.org/10.1016/j.molmed.2013.04.006 |
| [20] | Huang, F., Wang, M., Yang, T., et al. (2014) Gastric Cancer-Derived MSC-Secreted PDGF-DD Promotes Gastric Cancer Progression. Journal of Cancer Research and Clinical Oncology, 140, 1835-1848.
https://doi.org/10.1007/s00432-014-1723-2 |
| [21] | Wang, Y., Qiu, H., Hu, W., Li, S. and Yu, J. (2014) Over-Expression of Platelet-Derived Growth Factor-D Promotes Tumor Growth and Invasion in Endometrial Cancer. International Journal of Molecular Sciences, 15, 4780-4794.
https://doi.org/10.3390/ijms15034780 |
| [22] | Ustach, C.V. and Kim, H.R. (2005) Platelet-Derived Growth Factor D Is Activated by Urokinase Plasminogen Activator in Prostate Carcinoma Cells. Molecular and Cellular Biology, 25, 6279-6288.
https://doi.org/10.1128/MCB.25.14.6279-6288.2005 |
| [23] | Folestad, E., Kunath, A. and W？gs？ter, D. (2018) PDGF-C and PDGF-D Signaling in Vascular Diseases and Animal Models. Molecular Aspects of Medicine, 62, 1-11. https://doi.org/10.1016/j.mam.2018.01.005 |
| [24] | Ding, H., Wu, X., Bostr？m, H., et al. (2004) A Specific Require-ment for PDGF-C in Palate Formation and PDGFR-α Signaling. Nature Genetics, 36, 1111-1116. https://doi.org/10.1038/ng1415 |
| [25] | Andrae, J., Gallini, R. and Betsholtz, C. (2008) Role of Platelet-Derived Growth Factors in Physiology and Medicine. Genes & Development, 22, 1276-312. https://doi.org/10.1101/gad.1653708 |
| [26] | Pennock, S., Haddock, L.J., Eliott, D., Mukai, S. and Kazlauskas, A. (2014) Is Neutralizing Vitreal Growth Factors a Viable Strategy to Prevent Proliferative Vitreoretinopathy? Progress in Retinal and Eye Research, 40, 16-34.
https://doi.org/10.1016/j.preteyeres.2013.12.006 |
| [27] | Chen, H., Gu, X., Liu, Y., et al. (2011) PDGF Signalling Controls Age-Dependent Proliferation in Pancreatic Β-Cells. Nature, 478, 349-355. https://doi.org/10.1038/nature10502 |
| [28] | Liu, X., Zhang, F., Chai, Y., Wang, L. and Yu, B. (2020) The Role of Bone-Derived PDGF-AA in Age-Related Pancreatic β Cell Proliferation and Function. Biochemical and Biophysical Re-search Communications, 524, 22-27.
https://doi.org/10.1016/j.bbrc.2019.12.057 |
| [29] | Abderrahmani, A., Yengo, L., Caiazzo, R., et al. (2018) Increased Hepatic PDGF-AA Signaling Mediates Liver Insulin Resistance in Obesity-Associated Type 2 Diabetes. Diabetes, 67, 1310-1321. https://doi.org/10.2337/db17-1539 |
| [30] | Watanabe, E., Wada, T., Okekawa, A., et al. (2020) Stromal Cell-Derived Factor 1 (SDF1) Attenuates Platelet-Derived Growth Factor-B (PDGF-B)-Induced Vascular Remodeling for Adipose Tissue Expansion in Obesity. Angiogenesis, 23, 667-684. https://doi.org/10.1007/s10456-020-09738-6 |
| [31] | Onogi, Y., Wada, T., Okekawa, A., et al. (2020) Pro-Inflammatory Macrophages Coupled with Glycolysis Remodel Adipose Vasculature by Producing Platelet-Derived Growth Factor-B in Obesity. Scientific Reports, 10, Article No. 670. https://doi.org/10.1038/s41598-019-57368-w |
| [32] | Onogi, Y., Wada, T., Kamiya, C., et al. (2017) PDGFRβ Regu-lates Adipose Tissue Expansion and Glucose Metabolism via Vascular Remodeling in Diet-Induced Obesity. Diabetes, 66, 1008-1021. https://doi.org/10.2337/db16-0881 |
| [33] | Shao, M., Vishvanath, L., Busbuso, N.C., et al. (2018) De Novo Adipocyte Differentiation from Pdgfrβ+ Preadipocytes Protects against Pathologic Visceral Adipose Expansion in Obesity. Nature Communications, 9, Article No. 890.
https://doi.org/10.1038/s41467-018-03196-x |
| [34] | Wang, X., Yi, X. and Tang, D. (2021) Regular Aerobic Exercise Activates PDGF-BB/PDGFR-β Signaling and Modulates the Inflammatory-Anti-Inflammatory Balance in Diet-Induced Obese Mice. Obesity Research & Clinical Practice, 15, 387-394. https://doi.org/10.1016/j.orcp.2021.04.003 |
| [35] | Hou, X., Kumar, A., Lee, C., et al. (2010) PDGF-CC Blockade In-hibits Pathological Angiogenesis by Acting on Multiple Cellular and Molecular Targets. Proceedings of the National Academy of Sciences of the United States of America, 107, 12216-12221. https://doi.org/10.1073/pnas.1004143107 |
| [36] | Crawford, Y., Kasman, I., Yu, L., et al. (2009) PDGF-C Mediates the Angiogenic and Tumorigenic Properties of Fibroblasts Associated with Tumors Refractory to Anti-VEGF Treatment. Cancer Cell, 15, 21-34.
https://doi.org/10.1016/j.ccr.2008.12.004 |
| [37] | Moriya, J., Wu, X., Zavala-Solorio, J., et al. (2014) Platelet-Derived Growth Factor C Promotes Revascularization in Ischemic Limbs of Diabetic Mice. Journal of Vascular Surgery, 59, 1402-1409.
https://doi.org/10.1016/j.jvs.2013.04.053 |
| [38] | Cox, N., Crozet, L., Holtman, I.R., et al. (2021) Diet-Regulated Production of PDGFcc by Macrophages Controls Energy Storage. Science, 373, eabe9383. https://doi.org/10.1126/science.abe9383 |
| [39] | Seki, T., Hosaka, K., Lim, S., et al. (2016) Endothelial PDGF-CC Regulates Angiogenesis-Dependent Thermogenesis in Beige Fat. Nature Communications, 7, Article No. 12152. https://doi.org/10.1038/ncomms12152 |
| [40] | Chen, Z., Yu, H., Shi, X., et al. (2020) Functional Screening of Candi-date Causal Genes for Insulin Resistance in Human Preadipocytes and Adipocytes. Circulation Research, 126, 330-346.
https://doi.org/10.1161/CIRCRESAHA.119.315246 |
| [41] | Thomas, J.A., Deaton, R.A., Hastings, N.E., et al. (2009) PDGF-DD, a Novel Mediator of Smooth Muscle Cell Phenotypic Modulation, Is Upregulated in Endothelial Cells Ex-posed to Atherosclerosis-Prone Flow Patterns. American Journal of Physiology-Heart and Circulatory Physiology, 296, H442-H452.
https://doi.org/10.1152/ajpheart.00165.2008 |
| [42] | Kapur, S.K., Dos-Anjos Vilaboa, S., Llull, R. and Katz, A.J. (2015) Adipose Tissue and Stem/Progenitor Cells: Discovery and Development. Clinics in Plastic Surgery, 42, 155-167. https://doi.org/10.1016/j.cps.2014.12.010 |
| [43] | Kim, J.H., Park, S.G., Kim, W.-K., Song, S.U. and Sung, J.-H. (2015) Functional Regulation of Adipose-Derived Stem Cells by PDGF-D. Stem Cells, 33, 542-556. https://doi.org/10.1002/stem.1865 |
| [44] | Kovacevic, D., Gulotta, L.V., Ying, L., et al. (2015) RhPDGF-BB Pro-motes Early Healing in a Rat Rotator Cuff Repair Model. Clinical Orthopaedics and Related Research, 473, 1644-1654. https://doi.org/10.1007/s11999-014-4020-0 |
| [45] | Daniels, T.R., Younger, A.S., Penner, M.J., et al. (2015) Pro-spective Randomized Controlled Trial of Hindfoot and Ankle Fusions Treated with rhPDGF-BB in Combination with a β-TCP-Collagen Matrix. Foot & Ankle International, 36, 739-748. https://doi.org/10.1177/1071100715576370 |
| [46] | Pardanani, A., D’Souza, A., Knudson, R.A., et al. (2012) Long-Term Follow-up of FIP1L1-PDGFRA-Mutated Patients with Eosinophilia: Survival and Clinical Outcome. Leuke-mia, 26, 2439-2441. https://doi.org/10.1038/leu.2012.162 |
| [47] | Han, M.S., Chung, K.W., Cheon, H.G., et al. (2009) Imatinib Mesylate Reduces Endoplasmic Reticulum Stress and Induces Remission of Diabetes in db/db Mice. Diabetes, 58, 329-336. https://doi.org/10.2337/db08-0080 |
| [48] | Choi, S.-S., Kim, E.-S., Jung, J.-E., et al. (2016) PPARγ An-tagonist Gleevec Improves Insulin Sensitivity and Promotes the Browning of White Adipose Tissue. Diabetes, 65, 829-839. https://doi.org/10.2337/db15-1382 |
| [49] | Gitelman, S.E., Bundy, B.N., Ferrannini, E., et al. (2021) Imatinib Therapy for Patients with Recent-Onset Type 1 Diabetes: A Multicentre, Randomised, Double-Blind, Place-bo-Controlled, Phase 2 Trial. The Lancet Diabetes and Endocrinology, 9, 502-514. https://doi.org/10.1016/S2213-8587(21)00139-X |
| [50] | Jing, Y., Wu, F., Li, D., et al. (2018) Metformin Improves Obesity-Associated Inflammation by Altering Macrophages Polarization. Molecular and Cellular Endocrinology, 461, 256-264. https://doi.org/10.1016/j.mce.2017.09.025 |
| [51] | Soccio, R.E., Li, Z., Chen, E.R., et al. (2017) Target-ingPPARγ in the Epigenome Rescues Genetic Metabolic Defects in Mice. Journal of Clinical Investigation, 127, 1451-1462. https://doi.org/10.1172/JCI91211 |
