Research progress on the role of KLF2 in liver diseases_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YE Qifa , WANG Hongyu , LUO Jun ,  LIU Zhongzhong

Institute of Hepatobiliary Diseases of Wuhan University, Zhongnan Hospital of Wuhan University, Transplant Center of Wuhan University, National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-Based Medical Materials, Wuhan 430071, P. R. China;

Corresponding author：

LIU Zhongzhong, Email: liuzhongzhong28@163.com

Keywords：

Kruppel-like factor 2; liver disease; ischemia-reperfusion injury

DOI：

10.7507/1007-9424.202206008

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the mechanism and research progress of Kruppel-like factor 2 (KLF2) in various liver diseases and related drug development, providing theoretical basis for further mechanism exploration and clinical application. Method The literatures on the mechanism of KLF2 in liver diseases at home and abroad were collected and summarized. Results KLF2 was widely distributed and had various functions in human body, mainly regulating the growth, differentiation and function of endothelial cells, inhibiting pro-inflammatory and pro-thrombotic gene expression, and participating in important physiological processes such as liver inflammation, oxidative stress and thrombosis, and affecting the occurrence and development of various liver diseases. The regulation of KLF2 expression by statins had been widely used in the treatment of liver diseases. Conclusion KLF2 regulates the expression of related molecules through a variety of pathways and affects the functions of various cells in the liver, which is the focus of research on improving liver injury.

Citation： YE Qifa, WANG Hongyu, LUO Jun, LIU Zhongzhong. Research progress on the role of KLF2 in liver diseases. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(11): 1516-1521. doi: 10.7507/1007-9424.202206008 Copy

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2. Pearson R, Fleetwood J, Eaton S, et al. Krüppel-like transcription factors: a functional family. Int J Biochem Cell Biol, 2008, 40(10): 1996-2001.
3. Boon RA, Urbich C, Fischer A, et al. Kruppel-like factor 2 improves neovascularization capacity of aged proangiogenic cells. Eur Heart J, 2011, 32(3): 371-377.
4. Chiplunkar AR, Curtis BC, Eades GL, et al. The Krüppel-like factor 2 and Krüppel-like factor 4 genes interact to maintain endothelial integrity in mouse embryonic vasculogenesis. BMC Dev Biol, 2013, 13: 40. doi: 10.1186/1471-213X-13-40.
5. Sangwung P, Zhou G, Nayak L, et al. KLF2 and KLF4 control endothelial identity and vascular integrity. JCI Insight, 2017, 2(4): e91700. doi: 10.1172/jci.insight.91700.
6. Thakar S, Katakia YT, Ramakrishnan SK, et al. Intermittent high glucose elevates nuclear localization of EZH2 to cause H3K27me3-dependent repression of KLF2 leading to endothelial inflammation. Cells, 2021, 10(10): 2548. doi: 10.3390/cells10102548.
7. Lin Z, Kumar A, SenBanerjee S, et al. Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function. Circ Res, 2005, 96(5): e48-e57.
8. Lin Z, Natesan V, Shi H, et al. Kruppel-like factor 2 regulates endothelial barrier function. Arterioscler Thromb Vasc Biol, 2010, 30(10): 1952-1959.
9. Doddaballapur A, Michalik KM, Manavski Y, et al. Laminar shear stress inhibits endothelial cell metabolism via KLF2-mediated repression of PFKFB3. Arterioscler Thromb Vasc Biol, 2015, 35(1): 137-145.
10. Yang Y, Mumau M, Tober J, et al. Endothelial MEKK3-KLF2/4 signaling integrates inflammatory and hemodynamic signals during definitive hematopoiesis. Blood, 2022, 139(19): 2942-2957.
11. Wang FF, Zhang JL, Ji Y, et al. KLF2 mediates the suppressive effect of BDNF on diabetic intimal calcification by inhibiting HK1 induced endothelial-to-mesenchymal transition. Cell Signal, 2022, 94: 110324. doi: 10.1016/j.cellsig.2022.110324.
12. Qin SY, Li B, Chen M, et al. MiR-32-5p promoted epithelial-to-mesenchymal transition of oral squamous cell carcinoma cells via regulating the KLF2/CXCR4 pathway. Kaohsiung J Med Sci, 2022, 38(2): 120-128.
13. Wittner J, Schuh W. Krüppel-like factor 2 (KLF2) in immune cell migration. Vaccines (Basel), 2021, 9(10): 1171. doi: 10.3390/vaccines9101171.
14. Marrone G, Maeso-Díaz R, García-Cardena G, et al. KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. Gut, 2015, 64(9): 1434-1443.
15. Chu HR, Sun YC, Gao Y, et al. Function of Krüppel-like factor 2 in the shear stress-induced cell differentiation of endothelial progenitor cells to endothelial cells. Mol Med Rep, 2019, 19(3): 1739-1746.
16. Dekker RJ, van Soest S, Fontijn RD, et al. Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Krüppel-like factor (KLF2). Blood, 2002, 100(5): 1689-1698.
17. Sathanoori R, Rosi F, Gu BJ, et al. Shear stress modulates endothelial KLF2 through activation of P2X4. Purinergic Signal, 2015, 11(1): 139-153.
18. Russo FP, Ferrarese A, Zanetto A. Recent advances in understanding and managing liver transplantation. F1000Res, 2016, 5: F1000 Faculty Rev-2895.1000v-2895v. doi: 10.12688/f1000research.8768.1.eCollection 2016.
19. Zhang W, Liu Z, Xu X. Navigating immune cell immunometabolism after liver transplantation. Crit Rev Oncol Hematol, 2021, 160: 103227. doi: 10.1016/j.critrevonc.2021.103227.
20. Czigany Z, Lurje I, Schmelzle M, et al. Ischemia-reperfusion injury in marginal liver grafts and the role of hypothermic machine perfusion: molecular mechanisms and clinical implications. J Clin Med, 2020, 9(3): 846. doi: 10.3390/jcm9030846.
21. Ye L, He S, Mao X, et al. Effect of hepatic macrophage polarization and apoptosis on liver ischemia and reperfusion injury during liver transplantation. Front Immunol, 2020, 11: 1193. doi:10.3389/fimmu.2020.01193.
22. Lentsch AB, Kato A, Yoshidome H, et al. Inflammatory mechanisms and therapeutic strategies for warm hepatic ischemia/reperfusion injury. Hepatology, 2000, 32(2): 169-173.
23. Guan Y, Yao W, Yi K, et al. Nanotheranostics for the management of hepatic ischemia-reperfusion injury. Small, 2021, 17(23): e2007727. doi: 10.1002/smll.202007727.
24. Wu W, Geng P, Zhu J, et al. KLF2 regulates eNOS uncoupling via Nrf2/HO-1 in endothelial cells under hypoxia and reoxygenation. Chem Biol Interact, 2019, 305: 105-111.
25. Chatauret N, Coudroy R, Delpech PO, et al. Mechanistic analysis of nonoxygenated hypothermic machine perfusion’s protection on warm ischemic kidney uncovers greater eNOS phosphorylation and vasodilation. Am J Transplant, 2014, 14(11): 2500-2514.
26. Hide D, Ortega-Ribera M, Garcia-Pagan JC, et al. Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy. Sci Rep, 2016, 6: 22107. doi: 10.1038/srep22107.
27. Nemeth N, Peto K, Magyar Z, et al. Hemorheological and microcirculatory factors in liver ischemia-reperfusion injury-an update on pathophysiology, molecular mechanisms and protective strategies. Int J Mol Sci, 2021, 22(4): 1864. doi: 10.3390/ijms22041864.
28. Wu F, Li C. KLF2 up-regulates IRF4/HDAC7 to protect neonatal rats from hypoxic-ischemic brain damage. Cell Death Discov, 2022, 8(1): 41. doi: 10.1038/s41420-022-00813-z.
29. Peralta C, Jiménez-Castro MB, Gracia-Sancho J. Hepatic ischemia and reperfusion injury: effects on the liver sinusoidal milieu. J Hepatol, 2013, 59(5): 1094-1106.
30. Gracia-Sancho J, Caparrós E, Fernández-Iglesias A, et al. Role of liver sinusoidal endothelial cells in liver diseases. Nat Rev Gastroenterol Hepatol, 2021, 18(6): 411-431.
31. Wuestenberg A, Kah J, Singethan K, et al. Matrix conditions and KLF2-dependent induction of heme oxygenase-1 modulate inhibition of HCV replication by fluvastatin. PLoS One, 2014, 9(5): e96533. doi: 10.1371/journal.pone.0096533.
32. Otterbein LE, Soares MP, Yamashita K, et al. Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol, 2003, 24(8): 449-455.
33. Selzner N, Rudiger H, Graf R, et al. Protective strategies against ischemic injury of the liver. Gastroenterology, 2003, 125(3): 917-936.
34. Qu S, Yuan B, Zhang H, et al. Heme oxygenase 1 attenuates hypoxia-reoxygenation injury in mice liver sinusoidal endothelial cells. Transplantation, 2018, 102(3): 426-432.
35. Boteon YL, Laing R, Mergental H, et al. Mechanisms of autophagy activation in endothelial cell and their targeting during normothermic machine liver perfusion. World J Gastroenterol, 2017, 23(48): 8443-8451.
36. Ruart M, Chavarria L, Campreciós G, et al. Impaired endothelial autophagy promotes liver fibrosis by aggravating the oxidative stress response during acute liver injury. J Hepatol, 2019, 70(3): 458-469.
37. Laha D, Deb M, Das H. KLF2 (kruppel-like factor 2 [lung]) regulates osteoclastogenesis by modulating autophagy. Autophagy, 2019, 15(12): 2063-2075.
38. Maity J, Deb M, Greene C, et al. KLF2 regulates dental pulp-derived stem cell differentiation through the induction of mitophagy and altering mitochondrial metabolism. Redox Biol, 2020, 36: 101622. doi: 10.1016/j.redox.2020.101622.
39. Ma C, Wu H, Yang G, et al. Calycosin ameliorates atherosclerosis by enhancing autophagy via regulating the interaction between KLF2 and MLKL in apolipoprotein E gene-deleted mice. Br J Pharmacol, 2022, 179(2): 252-269.
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