Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Upregulation of adiponectin by Ginsenoside Rb1 contributes to amelioration of hepatic steatosis induced by high fat diet

  • Li, Yaru (Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine) ;
  • Zhang, Shuchen (Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine) ;
  • Zhu, Ziwei (Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine) ;
  • Zhou, Ruonan (Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine) ;
  • Xu, Pingyuan (Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine) ;
  • Zhou, Lingyan (Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine) ;
  • Kan, Yue (Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine) ;
  • Li, Jiao (Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine) ;
  • Zhao, Juan (Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine) ;
  • Fang, Penghua (Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine) ;
  • Yu, Xizhong (Key Laboratory for Metabolic Diseases in Chinese Medicine, First College of Clinical Medicine, Nanjing University of Chinese Medicine) ;
  • Shang, Wenbin (Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine)
  • Received : 2021.08.03
  • Accepted : 2021.10.25
  • Published : 2022.07.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Ginsenoside Rb1 (GRb1) is capable of regulating lipid and glucose metabolism through its action on adipocytes. However, the beneficial role of GRb1-induced up-regulation of adiponectin in liver steatosis remains unelucidated. Thus, we tested whether GRb1 ameliorates liver steatosis and insulin resistance by promoting the expression of adiponectin. Methods: 3T3-L1 adipocytes and hepatocytes were used to investigate GRb1's action on adiponectin expression and triglyceride (TG) accumulation. Wild type (WT) mice and adiponectin knockout (KO) mice fed high fat diet were treated with GRb1 for 2 weeks. Hepatic fat accumulation and function as well as insulin sensitivity was measured. The activation of AMPK was also detected in the liver and hepatocytes. Results: GRb1 reversed the reduction of adiponectin secretion in adipocytes. The conditioned medium (CM) from adipocytes treated with GRb1 reduced TG accumulation in hepatocytes, which was partly attenuated by the adiponectin antibody. In the KO mice, the GRb1-induced significant decrease of TG content, ALT and AST was blocked by the deletion of adiponectin. The elevations of GRb1-induced insulin sensitivity indicated by OGTT, ITT and HOMA-IR were also weakened in the KO mice. The CM treatment significantly enhanced the phosphorylation of AMPK in hepatocytes, but not GRb1 treatment. Likewise, the phosphorylation of AMPK in liver of the WT mice was increased by GRb1, but not in the KO mice. Conclusions: The up-regulation of adiponectin by GRb1 contributes to the amelioration of liver steatosis and insulin resistance, which further elucidates a new mechanism underlying the beneficial effects of GRb1 on obesity.

Keywords

Acknowledgement

This study was supported by the National Natural Science Foundation of China (grant numbers 81503312, 81873060) and the Open Projects of the Discipline of Chinese Medicine of Nanjing University of Chinese Medicine Supported by the Subject of Academic priority discipline of Jiangsu Higher Education Institutions (ZYX03KF058). This study was also partly supported by Jiangsu Province Graduate Students Research and Innovation Plan (KYCX21_1665).

References

  1. Bence KK, Birnbaum MJ. Metabolic drivers of non-alcoholic fatty liver disease. Mol Metab 2020:101143.
  2. Birkenfeld AL, Shulman GI. Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology 2014;59:713-23. https://doi.org/10.1002/hep.26672
  3. Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of nonalcoholic fatty liver disease (NAFLD). Metabolism 2016;65:1038-48. https://doi.org/10.1016/j.metabol.2015.12.012
  4. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73-84. https://doi.org/10.1002/hep.28431
  5. Fan JG, Kim SU, Wong VW. New trends on obesity and NAFLD in Asia. J Hepatol 2017;67:862-73. https://doi.org/10.1016/j.jhep.2017.06.003
  6. Ferguson D, Finck BN. Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus. Nat Rev Endocrinol 2021;17(8):484-95. https://doi.org/10.1038/s41574-021-00507-z
  7. Azzu V, Vacca M, Virtue S, Allison M, Vidal-Puig A. Adipose tissue-liver cross talk in the control of whole-body metabolism: implications in nonalcoholic fatty liver disease. Gastroenterology 2020;158:1899-912. https://doi.org/10.1053/j.gastro.2019.12.054
  8. Alves-Bezerra M, Cohen DE. Triglyceride metabolism in the liver. Comp Physiol 2017;8:1-8.
  9. Ipsen DH, Lykkesfeldt J, Tveden-Nyborg P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci 2018;75:3313-27. https://doi.org/10.1007/s00018-018-2860-6
  10. Cao H. Adipocytokines in obesity and metabolic disease. J Endocrinol 2014;220:T47-59. https://doi.org/10.1530/JOE-13-0339
  11. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev 2005;26:439-51. https://doi.org/10.1210/er.2005-0005
  12. Polyzos SA, Kountouras J, Zavos C, Tsiaousi E. The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease. Diabetes Obes Metabol 2010;12:365-83. https://doi.org/10.1111/j.1463-1326.2009.01176.x
  13. Combs TP, Marliss EB. Adiponectin signaling in the liver. Rev Endocr Metab Disord 2014;15:137-47. https://doi.org/10.1007/s11154-013-9280-6
  14. Ratan ZA, Haidere MF, Hong YH, Park SH, Lee JO, Lee J, Cho JY. Pharmacological potential of ginseng and its major component ginsenosides. J Ginseng Res 2021;45:199-210. https://doi.org/10.1016/j.jgr.2020.02.004
  15. Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58:1685-93. https://doi.org/10.1016/S0006-2952(99)00212-9
  16. Lim W, Mudge KW, Vermeylen F. Effects of population, age, and cultivation methods on ginsenoside content of wild American ginseng (Panax quinquefolium). J Agric Food Chem 2005;53:8498-505. https://doi.org/10.1021/jf051070y
  17. Mohanan P, Subramaniyam S, Mathiyalagan R, Yang DC. Molecular signaling of ginsenosides Rb1, Rg1, and Rg3 and their mode of actions. J Ginseng Res 2018;42:123-32. https://doi.org/10.1016/j.jgr.2017.01.008
  18. Zhou P, Xie W, He S, Sun Y, Meng X, Sun G, Sun X. Ginsenoside Rb1 as an antidiabetic agent and its underlying mechanism analysis. Cells 2019;8.
  19. Lin N, Cai DL, Jin D, Chen Y, Shi JJ. Ginseng panaxoside Rb1 reduces body weight in diet-induced obese mice. Cell Biochem Biophys 2014;68:189-94. https://doi.org/10.1007/s12013-013-9688-3
  20. Shang W, Yang Y, Zhou L, Jiang B, Jin H, Chen M. Ginsenoside Rb1 stimulates glucose uptake through insulin-like signaling pathway in 3T3-L1 adipocytes. J Endocrinol 2008;198:561-9. https://doi.org/10.1677/JOE-08-0104
  21. Shang W, Yang Y, Jiang B, Jin H, Zhou L, Liu S, Chen M. Ginsenoside Rb1 promotes adipogenesis in 3T3-L1 cells by enhancing PPARgamma2 and C/EBPalpha gene expression. Life Sci 2007;80:618-25. https://doi.org/10.1016/j.lfs.2006.10.021
  22. Yu X, Ye L, Zhang H, Zhao J, Wang G, Guo C, Shang W. Ginsenoside Rb1 ameliorates liver fat accumulation by upregulating perilipin expression in adipose tissue of db/db obese mice. J Ginseng Res 2015;39:199-205. https://doi.org/10.1016/j.jgr.2014.11.004
  23. Shen L, Xiong Y, Wang DQ, Howles P, Basford JE, Wang J, Xiong YQ, Hui DY, Woods SC, Liu M. Ginsenoside Rb1 reduces fatty liver by activating AMP-activated protein kinase in obese rats. J Lipid Res 2013;54:1430-8. https://doi.org/10.1194/jlr.M035907
  24. Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, et al. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 2001;50:2094-9. https://doi.org/10.2337/diabetes.50.9.2094
  25. Li WC, Ralphs KL, Tosh D. Isolation and culture of adult mouse hepatocytes. Methods Mol Biol 2010;633:185-96. https://doi.org/10.1007/978-1-59745-019-5_13
  26. Xiong Y, Shen L, Liu KJ, Tso P, Xiong Y, Wang G, Woods SC, Liu M. Antiobesity and antihyperglycemic effects of ginsenoside Rb1 in rats. Diabetes 2010;59:2505-12. https://doi.org/10.2337/db10-0315
  27. Fang H, Judd RL. Adiponectin regulation and function. Comp Physiol 2018;8:1031-63. https://doi.org/10.1002/cphy.c170046
  28. Guo R, Wang L, Zeng X, Liu M, Zhou P, Lu H, Lin H, Dong M. Aquaporin 7 involved in GINSENOSIDE-RB1-mediated anti-obesity via peroxisome proliferator-activated receptor gamma pathway. Nutr Metab 2020;17:69. https://doi.org/10.1186/s12986-020-00490-8
  29. Mu Q, Fang X, Li X, Zhao D, Mo F, Jiang G, Yu N, Zhang Y, Guo Y, Fu M, et al. Ginsenoside Rb1 promotes browning through regulation of PPARg in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2015;466:530-5. https://doi.org/10.1016/j.bbrc.2015.09.064
  30. Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest 2017;127:1-4. https://doi.org/10.1172/jci92035
  31. Chang E, Choi JM, Kim WJ, Rhee EJ, Oh KW, Lee WY, Park SE, Park SW, Park CY. Restoration of adiponectin expression via the ERK pathway in TNFalpha-treated 3T3-L1 adipocytes. Mol Med Rep 2014;10:905-10. https://doi.org/10.3892/mmr.2014.2278
  32. Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 2003;112:91-100. https://doi.org/10.1172/JCI200317797
  33. Wang M, Chen Y, Xiong Z, Yu S, Zhou B, Ling Y, Zheng Z, Shi G, Wu Y, Qian X. Ginsenoside Rb1 inhibits free fatty acids-induced oxidative stress and inflammation in 3T3-L1 adipocytes. Mol Med Rep 2017;16:9165-72. https://doi.org/10.3892/mmr.2017.7710
  34. Gao H, Kang N, Hu C, Zhang Z, Xu Q, Liu Y, Yang S. Ginsenoside Rb1 exerts anti-inflammatory effects in vitro and in vivo by modulating toll-like receptor 4 dimerization and NF-kB/MAPKs signaling pathways. Phytomedicine 2020;69:153197. https://doi.org/10.1016/j.phymed.2020.153197
  35. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002;8:1288-95. https://doi.org/10.1038/nm788
  36. Shen L, Haas M, Wang DQ, May A, Lo CC, Obici S, Tso P, Woods SC, Liu M. Ginsenoside Rb1 increases insulin sensitivity by activating AMP-activated protein kinase in male rats. Phys Rep 2015;3:e12543. https://doi.org/10.14814/phy2.12543
  37. Odani T, Tanizawa H, Takino Y. Studies on the absorption, distribution, excretion and metabolism of ginseng saponins. III. The absorption, distribution and excretion of ginsenoside Rb1 in the rat. Chem Pharm Bull (Tokyo) 1983;31:1059-66. https://doi.org/10.1248/cpb.31.1059
  38. Akao T, Kanaoka M, Kobashi K. Appearance of compound K, a major metabolite of ginsenoside Rb1 by intestinal bacteria, in rat plasma after oral administration-measurement of compound K by enzyme immunoassay. Biol Pharm Bull 1998;21:245-9. https://doi.org/10.1248/bpb.21.245
  39. Akao T, Kida H, Kanaoka M, Hattori M, Kobashi K. Intestinal bacterial hydrolysis is required for the appearance of compound K in rat plasma after oral administration of ginsenoside Rb1 from Panax ginseng. J Pharm Pharmacol 1998;50:1155-60. https://doi.org/10.1111/j.2042-7158.1998.tb03327.x
  40. Sharma A, Lee HJ. Ginsenoside compound K: insights into recent studies on pharmacokinetics and health-promoting activities. Biomolecules 2020;10.
  41. Yang XD, Yang YY, Ouyang DS, Yang GP. A review of biotransformation and pharmacology of ginsenoside compound K. Fitoterapia 2015;100:208-20. https://doi.org/10.1016/j.fitote.2014.11.019
  42. Wei S, Li W, Yu Y, Yao FAL, Lan X, Guan F, Zhang M, Chen L. Ginsenoside Compound K suppresses the hepatic gluconeogenesis via activating adenosine-5'monophosphate kinase: a study in vitro and in vivo. Life Sci 2015;139:8-15. https://doi.org/10.1016/j.lfs.2015.07.032
  43. Hwang YC, Oh DH, Choi MC, Lee SY, Ahn KJ, Chung HY, Lim SJ, Chung SH, Jeong IK. Compound K attenuates glucose intolerance and hepatic steatosis through AMPK-dependent pathways in type 2 diabetic OLETF rats. Korean J Intern Med 2018;33:347-55. https://doi.org/10.3904/kjim.2015.208
  44. Chen W, Wang J, Luo Y, Wang T, Li X, Li A, Li J, Liu K, Liu B. Ginsenoside Rb1 and compound K improve insulin signaling and inhibit ER stress-associated NLRP3 inflammasome activation in adipose tissue. J Ginseng Res 2016;40:351-8. https://doi.org/10.1016/j.jgr.2015.11.002
  45. Lee JO, Choi E, Shin KK, Hong YH, Kim HG, Jeong D, Hossain MA, Kim HS, Yi YS, Kim D, et al. Compound K, a ginsenoside metabolite, plays an antiinflammatory role in macrophages by targeting the AKT1-mediated signaling pathway. J Ginseng Res 2019;43:154-60. https://doi.org/10.1016/j.jgr.2018.10.003