Journal of Ginseng Research

  • 제47권3호
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  • Pages.429-439
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  • 2023
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  • 1226-8453(pISSN)
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  • 2093-4947(eISSN)
고려인삼학회 (The Korean Society of Ginseng)
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Ginsenoside Rg3-enriched Korean Red Ginseng extract attenuates Non-Alcoholic Fatty Liver Disease by way of suppressed VCAM-1 expression in liver sinusoidal endothelium

  • Seoung-Woo Lee (Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University) ;
  • Su-Min Baek (Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University) ;
  • Young-Jin Lee (Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University) ;
  • Tae-Un Kim (Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University) ;
  • Jae-Hyuk Yim (Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University) ;
  • Jun-Hyeok Son (Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University) ;
  • Hee-Yeon Kim (Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University) ;
  • Kyung-Ku Kang (Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation) ;
  • Jong Hun Kim (Department of Food Science and Biotechnology, Sungshin Women's University) ;
  • Man Hee Rhee (Laboratory of Veterinary Physiology and Cell Signaling, College of Veterinary Medicine, Kyungpook National University) ;
  • Sang-Joon Park (Laboratory of Veterinary Histology, College of Veterinary Medicine, Kyungpook National University) ;
  • Seong-Kyoon Choi (Core Protein Resources Center, Daegu-Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Jin-Kyu Park (Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University)
  • 투고 : 2022.09.07
  • 심사 : 2022.10.25
  • 발행 : 2023.05.01
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초록

Background: The incidence and clinical importance of nonalcoholic fatty liver disease (NAFLD) has emerged. However, effective therapeutic strategies for NAFLD have yet to be found. Panax ginseng (P. ginseng) is a traditional herb in Eastern Asia with therapeutic effects in many chronic disorders. However, the precise effects of ginseng extract on NAFLD are currently unknown. In present study, the therapeutic effects of Rg3-enriched red ginseng extract (Rg3-RGE) on the progression of NAFLD were explored. Methods: Twelve-week-old C57BL/6 male mice were fed a chow or western diet supplemented with high sugar water solution with or without Rg3-RGE. Histopathology, immunohistochemistry, immunofluorescence, serum biochemistry, western blot analysis, and quantitative RT-PCR were used for in vivo experiment. Conditionally immortalized human glomerular endothelial cell (CiGEnC) and primary liver sinusoidal endothelial cells (LSECs) were used for in vitro experiments. Results: Eight weeks of Rg3-RGE treatment significantly attenuated the inflammatory lesions of NAFLD. Furthermore, Rg3-RGE inhibited the inflammatory infiltrate in liver parenchyma and the expression of adhesive molecules to LSECs. Moreover, the Rg3-RGE exhibited similar patterns on the in vitro assays. Conclusion: The results demonstrate that Rg3-RGE treatment ameliorates NAFLD progression by inhibiting chemotaxis activities in LSECs.

키워드

과제정보

This work was supported by the 2020 grant from The Korean Society of Ginseng, the DGIST R&D Program of the Ministry of Science and ICT (2020010096), and National Research Foundation of Korea (NRF) of the Ministry of Education (2019R1I1A2A01060031).

참고문헌

  1. Kim C-H, Younossi ZM. Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome. Cleve Clin J Med 2008;75:721-8.  https://doi.org/10.3949/ccjm.75.10.721
  2. Abd El-Kader SM, El-Den Ashmawy EMS. Non-alcoholic fatty liver disease: the diagnosis and management. World J Hepatol 2015;7:846. 
  3. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221-31.  https://doi.org/10.1056/NEJMra011775
  4. Gerges SH, Wahdan SA, Elsherbiny DA, El-Demerdash E. Non-alcoholic fatty liver disease: an overview of risk factors, pathophysiological mechanisms, diagnostic procedures, and therapeutic interventions. Life Sci 2021;271:119220. 
  5. Arab JP, Arrese M, Trauner M. Recent insights into the pathogenesis of nonalcoholic fatty liver disease. Annu Rev Pathol: Mech Dis 2018;13:321-50.  https://doi.org/10.1146/annurev-pathol-020117-043617
  6. Yu A, Keeffe EB. Nonalcoholic fatty liver disease. Rev Gastroenterol Disord 2002;2:11-9. 
  7. Harrison SA, Day CP. Benefits of lifestyle modification in NAFLD. Gut 2007;56:1760-9.  https://doi.org/10.1136/gut.2006.112094
  8. Le MH, Yeo YH, Li X, Li J, Zou B, Wu Y, Ye Q, Huang DQ, Zhao C, Zhang J. Global NAFLD prevalence-A systematic review and meta-analysis. Clin Gastroenterol Hepatol 2019. 2021. 
  9. Mantovani A, Dalbeni A. Treatments for NAFLD: state of art. Int J Mol Sci 2021;22:2350. 
  10. Zhang C, Yang M. Current options and future directions for NAFLD and NASH treatment. Int J Mol Sci 2021;22:7571. 
  11. Targher G, Corey KE, Byrne CD. NAFLD, and cardiovascular and cardiac diseases: factors influencing risk, prediction and treatment. Diabetes Metab 2021;47:101215. 
  12. Zhang H, Abid S, Ahn JC, Mathiyalagan R, Kim Y-J, Yang D-C, Wang Y. Characteristics of panax ginseng cultivars in Korea and China. Molecules 2020;25:2635. 
  13. Park HJ, Kim DH, Park SJ, Kim JM, Ryu JH. Ginseng in traditional herbal prescriptions. J Ginseng Res 2012;36:225. 
  14. Im D-S. Pro-resolving effect of ginsenosides as an anti-inflammatory mechanism of Panax ginseng. Biomolecules 2020;10:444. 
  15. Tong Y, Song X, Zhang Y, Xu Y, Liu Q. Insight on structural modification, biological activity, structure-activity relationship of PPD-type ginsenoside derivatives. Fitoterapia 2022:105135. 
  16. Liu L, Zhu X-M, Wang Q-J, Zhang D-L, Fang Z-M, Wang C-Y, Wang Z, Sun B-S, Wu H, Sung C-K. Enzymatic preparation of 20 (S, R)-protopanaxadiol by transformation of 20 (S, R)-Rg3 from black ginseng. Phytochemistry 2010;71:1514-20.  https://doi.org/10.1016/j.phytochem.2010.05.007
  17. Lee H, Kong G, Tran Q, Kim C, Park J, Park J. Relationship between ginsenoside Rg3 and metabolic syndrome. Front Pharmacol 2020;11:130. 
  18. Saba E, Jeong D, Irfan M, Lee YY, Park S-J, Park C-K, Rhee MH. Anti-inflammatory activity of Rg3-enriched Korean red ginseng extract in murine model of sepsis. Evid Based Complement Alternat Med 2018;2018. 
  19. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313-21.  https://doi.org/10.1002/hep.20701
  20. Baek SM, Lee SW, Lee YJ, Choi SK, Kim HY, Seo MS, Sung SE, Lee AR, Kim TU, Han SH, et al. Vitamin C alleviates alcoholic liver injury by suppressing neutrophil infiltration in senescence marker protein 30-knockout mice irrespective of its antioxidant effects. Life Sci 2022;297:120228. 
  21. Tomita Y, Cakir B, Liu C-H, Fu Z, Huang S, Cho SS, Britton WR, Sun Y, Puder M, Hellstrom A. Free fatty acid receptor 4 activation protects against choroidal neovascularization in mice. Angiogenesis 2020;23:385-94.  https://doi.org/10.1007/s10456-020-09717-x
  22. Bertola A, Park O, Gao B. Chronic plus binge ethanol feeding synergistically induces neutrophil infiltration and liver injury in mice: a critical role for E-selectin. Hepatology 2013;58:1814-23.  https://doi.org/10.1002/hep.26419
  23. Mandrekar P, Ambade A, Lim A, Szabo G, Catalano D. An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice. Hepatology 2011;54:2185-97.  https://doi.org/10.1002/hep.24599
  24. Wan J, Benkdane M, Teixeira-Clerc F, Bonnafous S, Louvet A, Lafdil F, Pecker F, Tran A, Gual P, Mallat A. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology 2014;59:130-42.  https://doi.org/10.1002/hep.26607
  25. Park JK, Shao M, Kim MY, Baik SK, Cho MY, Utsumi T, Satoh A, Ouyang X, Chung C, Iwakiri Y. An endoplasmic reticulum protein, Nogo-B, facilitates alcoholic liver disease through regulation of kupffer cell polarization. Hepatology 2017;65:1720-34.  https://doi.org/10.1002/hep.29051
  26. Wree A, McGeough MD, Inzaugarat ME, Eguchi A, Schuster S, Johnson CD, Pena CA, Geisler LJ, Papouchado BG, Hoffman HM. NLRP3 inflammasome driven liver injury and fibrosis: roles of IL-17 and TNF in mice. Hepatology 2018;67:736-49.  https://doi.org/10.1002/hep.29523
  27. Girbl T, Lenn T, Perez L, Rolas L, Barkaway A, Thiriot A, Del Fresno C, Lynam E, Hub E, Thelen M. Distinct compartmentalization of the chemokines CXCL1 and CXCL2 and the atypical receptor ACKR1 determine discrete stages of neutrophil diapedesis. Immunity 2018;49:1062-1076. e6.  https://doi.org/10.1016/j.immuni.2018.09.018
  28. Sasaki M, Miyakoshi M, Sato Y, Nakanuma Y. Modulation of the microenvironment by senescent biliary epithelial cells may be involved in the pathogenesis of primary biliary cirrhosis. J Hepatol 2010;53:318-25.  https://doi.org/10.1016/j.jhep.2010.03.008
  29. Lassailly G, Saleh MB, Leleu-Chavain N, Ningarhari M, Gantier E, Carpentier R, Artru F, Gnemmi V, Bertin B, Maboudou P. Nucleotide-binding oligomerization domain 1 (NOD1) modulates liver ischemia reperfusion through the expression adhesion molecules. J Hepatol 2019;70:1159-69.  https://doi.org/10.1016/j.jhep.2019.01.019
  30. Yang Y, Sangwung P, Kondo R, Jung Y, McConnell MJ, Jeong J, Utsumi T, Sessa WC, Iwakiri Y. Alcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcohol-related liver disease. J Hepatol 2021;75:377-86.  https://doi.org/10.1016/j.jhep.2021.02.028
  31. Ishibashi H, Nakamura M, Komori A, Migita K, Shimoda S. Liver architecture, cell function, and disease. Semin Immunopathol 2009;31:399-409.  https://doi.org/10.1007/s00281-009-0155-6
  32. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010;52:1836-46.  https://doi.org/10.1002/hep.24001
  33. Xu L, Liu W, Bai F, Xu Y, Liang X, Ma C, Gao L. Hepatic macrophage as a key player in fatty liver disease. Front Immunol 2021:12. 
  34. Kazankov K, Jorgensen SMD, Thomsen KL, Moller HJ, Vilstrup H, George J, Schuppan D, Gronbaek H. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol 2019;16:145-59.  https://doi.org/10.1038/s41575-018-0082-x
  35. Li H. Intercellular crosstalk of liver sinusoidal endothelial cells in liver fibrosis, cirrhosis and hepatocellular carcinoma. Dig Liver Dis 2021. 
  36. Poisson J, Lemoinne S, Boulanger C, Durand F, Moreau R, Valla D, Rautou P-E. Liver sinusoidal endothelial cells: physiology and role in liver diseases. J Hepatol 2017;66:212-27.  https://doi.org/10.1016/j.jhep.2016.07.009
  37. Martin-Armas M, Simon-Santamaria J, Pettersen I, Moens U, Smedsrod B, Sveinbjornsson B. Toll-like receptor 9 (TLR9) is present in murine liver sinusoidal endothelial cells (LSECs) and mediates the effect of CpG-oligonucleotides. J Hepatol 2006;44:939-46.  https://doi.org/10.1016/j.jhep.2005.09.020
  38. Shetty S, Lalor PF, Adams DH. Liver sinusoidal endothelial cells-gatekeepers of hepatic immunity. Nat Rev Gastroenterol Hepatol 2018;15:555-67.  https://doi.org/10.1038/s41575-018-0020-y
  39. Ibrahim SH. Sinusoidal endotheliopathy in nonalcoholic steatohepatitis: therapeutic implications. Am J Physiol - Gastrointest 2021;321:G67-74.  https://doi.org/10.1152/ajpgi.00009.2021
  40. Furuta K, Guo Q, Pavelko KD, Lee J-H, Robertson KD, Nakao Y, Melek J, Shah VH, Hirsova P, Ibrahim SH. Lipid-induced endothelial vascular cell adhesion molecule 1 promotes nonalcoholic steatohepatitis pathogenesis. J Clin Invest 2021:131. 
  41. Furuta K, Guo Q, Hirsova P, Ibrahim SH. Emerging roles of liver sinusoidal endothelial cells in nonalcoholic steatohepatitis. Biology 2020;9:395. 
  42. Lafoz E, Ruart M, Anton A, Oncins A, Hernandez-Gea V. The endothelium as a driver of liver fibrosis and regeneration. Cells 2020;9:929. 
  43. Asgeirsd ottir SA, Talman EG, de Graaf IA, Kamps JA, Satchell SC, Mathieson PW, Ruiters MH, Molema G. Targeted transfection increases siRNA uptake and gene silencing of primary endothelial cells in vitro-a quantitative study. J Control Release 2010;141:241-51.  https://doi.org/10.1016/j.jconrel.2009.09.008
  44. Rhim JS, Tsai W, Chen Z, Chen Z, Van Waes C, Burger AM, Lautenberger JA. A human vascular endothelial cell model to study angiogenesis and tumorigenesis. Carcinogenesis 1998;19:673-81.  https://doi.org/10.1093/carcin/19.4.673
  45. Onat D, Brillon D, Colombo PC, Schmidt AM. Human vascular endothelial cells: a model system for studying vascular inflammation in diabetes and atherosclerosis. Curr Diab Rep 2011;11:193-202.  https://doi.org/10.1007/s11892-011-0182-2
  46. Bachetti T, Morbidelli L. Endothelial cells in culture: a model for studying vascular functions. Pharmacol Res 2000;42:9-19.  https://doi.org/10.1006/phrs.1999.0655
  47. Cho Y-S, Kim CH, Kim HN, Ha T-S, Ahn HY. Ginsenoside Rg3 inhibits lipopolysaccharide-induced adhesion molecule expression in human umbilical vein endothelial cell and C57BL/6 mice. Pharmazie 2014;69:818-22. 
  48. Geng J, Fu W, Yu X, Lu Z, Liu Y, Sun M, Yu P, Li X, Fu L, Xu H. Ginsenoside Rg3 alleviates ox-LDL induced endothelial dysfunction and prevents atherosclerosis in ApoE-/- mice by regulating PPARγ/FAK signaling pathway. Front Pharmacol 2020;11:500. 
  49. Liu Z, Bian X, Gao W, Su J, Ma C, Xiao X, Yu T, Zhang H, Liu X, Fan G. Rg3 promotes the SUMOylation of SERCA2a and corrects cardiac dysfunction in heart failure. Pharmacol Res 2021;172:105843. 
  50. Xue Q, He N, Wang Z, Fu X, Aung LHH, Liu Y, Li M, Cho JY, Yang Y, Yu T. Functional roles and mechanisms of ginsenosides from Panax ginseng in atherosclerosis.J Ginseng Res 202;45:22-31.