Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Ginsenosides Rc, as a novel SIRT6 activator, protects mice against high fat diet induced NAFLD

  • Zehong Yang (Artemisinin Research Center, Guangzhou University of Chinese Medicine) ;
  • Yuanyuan Yu (Artemisinin Research Center, Guangzhou University of Chinese Medicine) ;
  • Nannan Sun (Science and Technology Innovation Center, Guangzhou University of Chinese Medicine) ;
  • Limian Zhou (Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University) ;
  • Dong Zhang (Science and Technology Innovation Center, Guangzhou University of Chinese Medicine) ;
  • HaiXin Chen (Artemisinin Research Center, Guangzhou University of Chinese Medicine) ;
  • Wei Miao (Science and Technology Innovation Center, Guangzhou University of Chinese Medicine) ;
  • Weihang Gao (Science and Technology Innovation Center, Guangzhou University of Chinese Medicine) ;
  • Canyang Zhang (Science and Technology Innovation Center, Guangzhou University of Chinese Medicine) ;
  • Changhui Liu (School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine) ;
  • Xiaoying Yang (Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University) ;
  • Xiaojie Wu (Central lab of Binzhou People's Hospital) ;
  • Yong Gao (Science and Technology Innovation Center, Guangzhou University of Chinese Medicine)
  • Received : 2020.03.05
  • Accepted : 2020.07.29
  • Published : 2023.05.01
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Abstract

Background: Hepatic lipid disorder impaired mitochondrial homeostasis and intracellular redox balance, triggering development of non-alcohol fatty liver disease (NAFLD), while effective therapeutic approach remains inadequate. Ginsenosides Rc has been reported to maintain glucose balance in adipose tissue, while its role in regulating lipid metabolism remain vacant. Thus, we investigated the function and mechanism of ginsenosides Rc in defending high fat diet (HFD)-induced NAFLD. Methods: Mice primary hepatocytes (MPHs) challenged with oleic acid & palmitic acid were used to test the effects of ginsenosides Rc on intracellular lipid metabolism. RNAseq and molecular docking study were performed to explore potential targets of ginsenosides Rc in defending lipid deposition. Wild type and liver specific sirtuin 6 (SIRT6, 50721) deficient mice on HFD for 12 weeks were subjected to different dose of ginsenosides Rc to determine the function and detailed mechanism in vivo. Results: We identified ginsenosides Rc as a novel SIRT6 activator via increasing its expression and deacetylase activity. Ginsenosides Rc defends OA&PA-induced lipid deposition in MPHs and protects mice against HFD-induced metabolic disorder in dosage dependent manner. Ginsenosides Rc (20mg/kg) injection improved glucose intolerance, insulin resistance, oxidative stress and inflammation response in HFD mice. Ginsenosides Rc treatment accelerates peroxisome proliferator activated receptor alpha (PPAR-α, 19013)-mediated fatty acid oxidation in vivo and in vitro. Hepatic specific SIRT6 deletion abolished ginsenoside Rc-derived protective effects against HFD-induced NAFLD. Conclusion: Ginsenosides Rc protects mice against HFD-induced hepatosteatosis by improving PPAR-α-mediated fatty acid oxidation and antioxidant capacity in a SIRT6 dependent manner, and providing a promising strategy for NAFLD.

Keywords

Acknowledgement

We thank Professor Yongsheng Chang for providing us the mice with floxed alleles of SIRT6. This work was supported by the National Natural Science Foundation of China (grant nos. 81773969, 81102883 and 81800718), the First-class discipline construction major project of Guangzhou University of Chinese Medicine (Guangzhou University of Chinese Medicine Planning (2018, No.6), Guangzhou University of Chinese Medicine Planning (2019, No.5), the Guangdong Science and Technology Collaborative Innovation Center for Sport Science (2019B110210004), the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (No. 18KJB310015), the Jiangsu Shuangchuang Program, and the Starting Foundation for Talents of Xuzhou Medical University (No. D2018006). The Key R & D plan of Shandong Province (2019GSF108270)

References

  1. Nasr P, Fredrikson M, Ekstedt M, Kechagias S. The amount of liver fat predicts mortality and development of type 2 diabetes in non-alcoholic fatty liver disease. Liver International : Off J International Assoc Study Liver 2020. 
  2. Albano E, Mottaran E, Vidali M, Reale E, Saksena S, Occhino G, Burt AD, Day CP. Immune response towards lipid peroxidation products as a predictor of progression of non-alcoholic fatty liver disease to advanced fibrosis. Gut 2005;54:987-93.  https://doi.org/10.1136/gut.2004.057968
  3. Cave M, Deaciuc I, Mendez C, Song Z, Joshi-Barve S, Barve S, McClain C. Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition. J Nutritional Biochem 2007;18:184-95.  https://doi.org/10.1016/j.jnutbio.2006.12.006
  4. Brunt EM. Pathology of nonalcoholic fatty liver disease. Nature Reviews Gastroenterology Hepatology 2010;7:195-203.  https://doi.org/10.1038/nrgastro.2010.21
  5. Li JS, Wang WJ, Sun Y, Zhang YH, Zheng L. Ursolic acid inhibits the development of nonalcoholic fatty liver disease by attenuating endoplasmic reticulum stress. Food Function 2015;6:1643-51.  https://doi.org/10.1039/C5FO00083A
  6. Diraison F, Moulin P, Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease. Diabetes Metabolism 2003;29:478-85.  https://doi.org/10.1016/S1262-3636(07)70061-7
  7. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clinical Investigation 2005;115:1343-51.  https://doi.org/10.1172/JCI23621
  8. Kersten S. Integrated physiology and systems biology of PPARalpha. Molecular Metabolism 2014;3:354-71.  https://doi.org/10.1016/j.molmet.2014.02.002
  9. Konig B, Koch A, Spielmann J, Hilgenfeld C, Hirche F, Stangl GI, Eder K. Activation of PPARalpha and PPARgamma reduces triacylglycerol synthesis in rat hepatoma cells by reduction of nuclear SREBP-1. European J Pharmacology 2009;605:23-30.  https://doi.org/10.1016/j.ejphar.2009.01.009
  10. Konig B, Koch A, Spielmann J, Hilgenfeld C, Stangl GI, Eder K. Activation of PPARalpha lowers synthesis and concentration of cholesterol by reduction of nuclear SREBP-2. Biochemical Pharmacol 2007;73:574-85.  https://doi.org/10.1016/j.bcp.2006.10.027
  11. Chen L, Yang G. PPARs integrate the mammalian clock and energy metabolism. PPAR Res 2014;2014:653017. 
  12. Kaluski S, Portillo M, Besnard A, Stein D, Einav M, Zhong L, Ueberham U, Arendt T, Mostoslavsky R, Sahay A, et al. Neuroprotective functions for the histone deacetylase SIRT6. Cell Reports 2017;18:3052-62.  https://doi.org/10.1016/j.celrep.2017.03.008
  13. Martinez-Redondo V, Jannig PR, Correia JC, Ferreira DM, Cervenka I, Lindvall JM, Sinha I, Izadi M, Pettersson-Klein AT, Agudelo LZ, et al. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha isoforms selectively regulate multiple splicing events on target genes. J Biological Chem 2016;291:15169-84.  https://doi.org/10.1074/jbc.M115.705822
  14. Van Gool F, Galli M, Gueydan C, Kruys V, Prevot PP, Bedalov A, Mostoslavsky R, Alt FW, De Smedt T, Leo O. Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner. Nature Med 2009;15:206-10.  https://doi.org/10.1038/nm.1906
  15. Kuang J, Chen L, Tang Q, Zhang J, Li Y, He J. The role of Sirt6 in obesity and diabetes. Frontiers Physiology 2018;9:135. 
  16. Kim HS, Xiao C, Wang RH, Lahusen T, Xu X, Vassilopoulos A, Vazquez-Ortiz G, Jeong WI, Park O, Ki SH, et al. Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metabol 2010;12:224-36.  https://doi.org/10.1016/j.cmet.2010.06.009
  17. Naiman S, Huynh FK, Gil R, Glick Y, Shahar Y, Touitou N, Nahum L, Avivi MY, Roichman A, Kanfi Y, et al. SIRT6 promotes hepatic beta-oxidation via activation of PPARalpha. Cell Reports 2019;29:4127-4143 e4128. 
  18. Powell E, Kuhn P, Xu W. Nuclear receptor cofactors in PPARgamma-mediated adipogenesis and adipocyte energy metabolism. PPAR Res 2007;2007:53843. 
  19. Kim SK, Park JH. Trends in ginseng research in 2010. J Ginseng Res 2011;35:389-98.  https://doi.org/10.5142/jgr.2011.35.4.389
  20. Yang JW, Kim SS. Ginsenoside Rc promotes anti-adipogenic activity on 3T3-L1 adipocytes by down-regulating C/EBPalpha and PPARgamma. Molecules 2015;20:1293-303.  https://doi.org/10.3390/molecules20011293
  21. Ng TB, Wong CM, Yeung HW. Effect of ginsenosides Rg1, Rc and Rb2 on hormone-induced lipolysis and lipogenesis in rat epididymal fat cells. J Ethnopharmacol 1986;16:191-9.  https://doi.org/10.1016/0378-8741(86)90089-9
  22. Yu T, Rhee MH, Lee J, Kim SH, Yang Y, Kim HG, Kim Y, Kim C, Kwak YS, Kim JH, et al. Ginsenoside Rc from Korean red ginseng (panax ginseng C.A. Meyer) attenuates inflammatory symptoms of gastritis, hepatitis and arthritis. Am J Chin Med 2016;44:595-615.  https://doi.org/10.1142/S0192415X16500336
  23. Sun J, Wu W, Guo Y, Qin Q, Liu S. Pharmacokinetic study of ginsenoside Rc and simultaneous determination of its metabolites in rats using RRLC-Q-TOF-MS. J Pharm Biomed Anal 2014;88:16-21.  https://doi.org/10.1016/j.jpba.2013.08.015
  24. Chu Y, Zhang HC, Li SM, Wang JM, Wang XY, Li W, Zhang LL, Ma XH, Zhou SP, Zhu YH, et al. Determination of ginsenoside Rc in rat plasma by LC-MS/MS and its application to a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2013;919-920:75-8.  https://doi.org/10.1016/j.jchromb.2012.12.022
  25. Matsumoto M, Ogawa W, Teshigawara K, Inoue H, Miyake K, Sakaue H, Kasuga M. Role of the insulin receptor substrate 1 and phosphatidylinositol 3-kinase signaling pathway in insulin-induced expression of sterol regulatory element binding protein 1c and glucokinase genes in rat hepatocytes. Diabetes 2002;51:1672-80.  https://doi.org/10.2337/diabetes.51.6.1672
  26. Rector RS, Thyfault JP, Wei Y, Ibdah JA. Non-alcoholic fatty liver disease and the metabolic syndrome: an update. World Journal of Gastroenterology 2008;14:185-92.  https://doi.org/10.3748/wjg.14.185
  27. Heilbronn L, Smith SR, Ravussin E. Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus. International J Obesity Related Metabolic Disorders : J Int Assoc Study of Obesity 2004;28(Suppl 4):S12-21.  https://doi.org/10.1038/sj.ijo.0802853
  28. Lavoie JM, Gauthier MS. Regulation of fat metabolism in the liver: link to nonalcoholic hepatic steatosis and impact of physical exercise. Cellular Molecular Life Sciences : CMLS 2006;63:1393-409.  https://doi.org/10.1007/s00018-006-6600-y
  29. Cook WS, Yeldandi AV, Rao MS, Hashimoto T, Reddy JK. Less extrahepatic induction of fatty acid beta-oxidation enzymes by PPAR alpha. Biochemical Biophysical Res Comm 2000;278:250-7.  https://doi.org/10.1006/bbrc.2000.3739
  30. Kawahara TL, Michishita E, Adler AS, Damian M, Berber E, Lin M, McCord RA, Ongaigui KC, Boxer LD, Chang HY, et al. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 2009;136:62-74.  https://doi.org/10.1016/j.cell.2008.10.052
  31. Michishita E, McCord RA, Berber E, Kioi M, Padilla-Nash H, Damian M, Cheung P, Kusumoto R, Kawahara TL, Barrett JC, et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 2008;452:492-6.  https://doi.org/10.1038/nature06736
  32. Kanfi Y, Peshti V, Gil R, Naiman S, Nahum L, Levin E, Kronfeld-Schor N, Cohen HY. SIRT6 protects against pathological damage caused by diet-induced obesity. Aging Cell 2010;9:162-73.  https://doi.org/10.1111/j.1474-9726.2009.00544.x
  33. Grattagliano I, de Bari O, Bernardo TC, Oliveira PJ, Wang DQ, Portincasa P. Role of mitochondria in nonalcoholic fatty liver disease-from origin to propagation. Clinical Biochemistry 2012;45:610-8.  https://doi.org/10.1016/j.clinbiochem.2012.03.024
  34. Hunter CA, Kartal F, Koc ZC, Murphy T, Kim JH, Denvir J, Koc EC. Mitochondrial oxidative phosphorylation is impaired in TALLYHO mice, a new obesity and type 2 diabetes animal model. The Int J Biochem Cell Biology 2019;116:105616. 
  35. Einer C, Hohenester S, Wimmer R, Wottke L, Artmann R, Schulz S, Gosmann C, Simmons A, Leitzinger C, Eberhagen C, et al. Mitochondrial adaptation in steatotic mice. Mitochondrion 2018;40:1-12. https://doi.org/10.1016/j.mito.2017.08.015