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Schisandrin A in Schisandra chinensis Upregulates the LDL Receptor by Inhibiting PCSK9 Protein Stabilization in Steatotic Model

  • Hyo-Jin Kim (Personalized Diet Research Group, Korea Food Research Institute) ;
  • Seon Kyeong Park (Personalized Diet Research Group, Korea Food Research Institute) ;
  • Soo Hyun Park (Personalized Diet Research Group, Korea Food Research Institute) ;
  • Yu Geon Lee (Personalized Diet Research Group, Korea Food Research Institute) ;
  • Jae-Ho Park (Personalized Diet Research Group, Korea Food Research Institute) ;
  • Jin-Taek Hwang (Personalized Diet Research Group, Korea Food Research Institute) ;
  • Min-Yu Chung (Department of Food and Nutrition, Gangseo University)
  • Received : 2023.06.28
  • Accepted : 2023.10.12
  • Published : 2024.02.28

Abstract

Schisandra chinensis extract (SCE) protects against hypocholesterolemia by inhibiting proprotein convertase subtilisin/kexin 9 (PCSK9) protein stabilization. We hypothesized that the hypocholesterolemic activity of SCE can be attributable to upregulation of the PCSK9 inhibition-associated low-density lipoprotein receptor (LDLR). Male mice were fed a low-fat diet or a Western diet (WD) containing SCE at 1% for 12 weeks. WD increased final body weight and blood LDL cholesterol levels as well as alanine transaminase and aspartate aminotransferase expression. However, SCE supplementation significantly attenuated the increase in blood markers caused by WD. SCE also attenuated WD-mediated increases in hepatic LDLR protein expression in the obese mice. In addition, SCE increased LDLR protein expression and attenuated cellular PCSK9 levels in HepG2 cells supplemented with delipidated serum (DLPS). Non-toxic concentrations of schisandrin A (SA), one of the active components of SCE, significantly increased LDLR expression and tended to decrease PCSK9 protein levels in DLPS-treated HepG2 cells. High levels of SA-mediated PCSK9 attenuation was not attributable to reduced PCSK9 gene expression, but was associated with free PCSK9 protein degradation in this cell model. Our findings show that PCSK9 secretion can be significantly reduced by SA treatment, contributing to reductions in free cholesterol levels.

Keywords

Acknowledgement

This study was supported by the Main Research Program of the Korea Food Research Institute (KFRI) and was funded by the Ministry of Science and ICT (E0210601-03).

References

  1. Joseph P, Leong D, McKee M, Anand SS, Schwalm JD, Teo K, et al. 2017. Reducing the global burden of cardiovascular disease, part 1: the epidemiology and risk factors. Circ. Res. 121: 677-694.  https://doi.org/10.1161/CIRCRESAHA.117.308903
  2. Roth GA, Johnson C, Abajobir A, Abd-Allah F, Abera SF, Abyu G, et al. 2017. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J. Am. Coll. Cardiol. 70: 1-25.  https://doi.org/10.1016/j.jacc.2017.04.052
  3. Herrington W, Lacey B, Sherliker P, Armitage J, Lewington S. 2016. Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease. Circ. Res. 118: 535-546.  https://doi.org/10.1161/CIRCRESAHA.115.307611
  4. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. 2010. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 376: 1670-1681.  https://doi.org/10.1016/S0140-6736(10)61350-5
  5. Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, et al. 2007. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 370: 1829-1839.  https://doi.org/10.1016/S0140-6736(07)61778-4
  6. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, et al. 2009. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 302: 1993-2000.  https://doi.org/10.1001/jama.2009.1619
  7. Hegsted DM, Ausman LM, Johnson JA, Dallal GE. 1993. Dietary fat and serum lipids: an evaluation of the experimental data. Am. J. Clin. Nutr. 57: 875-883.  https://doi.org/10.1093/ajcn/57.6.875
  8. Keys A, Anderson JT, Grande F. 1957. Prediction of serum-cholesterol responses of man to changes in fats in the diet. Lancet 273: 959-966.  https://doi.org/10.1016/S0140-6736(57)91998-0
  9. Clarke R, Frost C, Collins R, Appleby P, Peto R. 1997. Dietary lipids and blood cholesterol: quantitative meta-analysis of metabolic ward studies. BMJ 314: 112-117.  https://doi.org/10.1136/bmj.314.7074.112
  10. Dattilo AM, Kris-Etherton PM. 1992. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am. J. Clin. Nutr. 56: 320-328.  https://doi.org/10.1093/ajcn/56.2.320
  11. Patriki D, Saravi SSS, Camici GG, Liberale L, Beer JH. 2021. PCSK 9: a link between inflammation and atherosclerosis. Curr. Med. Chem. 29: 251-267.  https://doi.org/10.2174/0929867328666210707192625
  12. Leander K, Malarstig A, Van't Hooft FM, Hyde C, Hellenius ML, Troutt JS, et al. 2016. Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) predicts future risk of cardiovascular events independently of established risk factors. Circulation133: 1230-1239. 
  13. Ruscica M, Ferri N, Fogacci F, Rosticci M, Botta M, Marchiano S, et al. 2017. Circulating levels of proprotein convertase subtilisin/kexin type 9 and arterial stiffness in a large population sample: data from the brisighella heart study. J. Am. Heart Assoc. 6: e005764. 
  14. Horton JD, Cohen JC, Hobbs HH. 2007. Molecular biology of PCSK9: Its role in LDL metabolism. Trends Biochem. Sci. 32: 71-77.  https://doi.org/10.1016/j.tibs.2006.12.008
  15. Xu S, Luo S, Zhu Z, Xu J. 2019. Small molecules as inhibitors of PCSK9: current status and future challenges. Eur. J. Med. Chem. 162: 212-233.  https://doi.org/10.1016/j.ejmech.2018.11.011
  16. Szopa A, Ekiert R, Ekiert H. 2017. Current knowledge of Schisandra chinensis (Turcz.) Baill.(Chinese magnolia vine) as a medicinal plant species: a review on the bioactive components, pharmacological properties, analytical and biotechnological studies. Phytochem. Rev. 16: 195-218.  https://doi.org/10.1007/s11101-016-9470-4
  17. Kopustinskiene DM, Bernatoniene J. 2021. Antioxidant effects of Schisandra chinensis fruits and their active constituents. Antioxidants 10: 620. 
  18. Seo HJ, Ji SB, Kim SE, Lee GM, Moon SH, Jang DS, et al. 2020. Analysis of dibenzocyclooctadiene lignans in Omija Wine and Cheong by liquid chromatography-tandem mass spectrometry. Mass. Spectrom. Lett. 11: 30-35. 
  19. Jeong HJ, Lee HS, Kim KS, Kim YK, Yoon D, Park SW. 2008. Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J. Lipid. Res. 49: 399-409.  https://doi.org/10.1194/jlr.M700443-JLR200
  20. Hwang JT, Choi E, Choi HK, Park JH, Chung MY. 2021. The cholesterol-lowering effect of Capsella Bursa-Pastoris is mediated via SREBP2 and HNF-1alpha-regulated PCSK9 inhibition in obese mice and HepG2 cells. Foods 10: 408. 
  21. Morrison MC, Verschuren L, Salic K, Verheij J, Menke A, Wielinga PY, et al. 2018. Obeticholic acid modulates serum metabolites and gene signatures characteristic of human NASH and attenuates inflammation and fibrosis progression in Ldlr-/-.leiden mice. Hepatol. Commun. 2: 1513-1532.  https://doi.org/10.1002/hep4.1270
  22. Tengeler AC, Gart E, Wiesmann M, Arnoldussen IAC, van Duyvenvoorde W, Hoogstad M, et al. 2020. Propionic acid and not caproic acid, attenuates nonalcoholic steatohepatitis and improves (cerebro) vascular functions in obese Ldlr(-/-) .Leiden mice. FASEB J. 34: 9575-9593.  https://doi.org/10.1096/fj.202000455R
  23. Li H, Dong B, Park SW, Lee HS, Chen W, Liu J. 2009. Hepatocyte nuclear factor 1alpha plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine. J. Biol. Chem. 284: 28885-28895.  https://doi.org/10.1074/jbc.M109.052407
  24. Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK. 2012. The PCSK9 decade. J. Lipid. Res. 53: 2515-2524.  https://doi.org/10.1194/jlr.R026658
  25. Maxfield FR, Tabas I. 2005. Role of cholesterol and lipid organization in disease. Nature 438: 612-621.  https://doi.org/10.1038/nature04399
  26. Estronca LM, Filipe HA, Salvador A, Moreno MJ, Vaz WL. 2014. Homeostasis of free cholesterol in the blood: a preliminary evaluation and modeling of its passive transport. J. Lipid. Res. 55: 1033-1043.  https://doi.org/10.1194/jlr.M043067
  27. Rothblat GH, Phillips MC. 2010. High-density lipoprotein heterogeneity and function in reverse cholesterol transport. Curr. Opin. Lipidol. 21: 229-238.  https://doi.org/10.1097/MOL.0b013e328338472d
  28. Xu X, Zhang A, Halquist MS, Yuan X, Henderson SC, Dewey WL, et al. 2017. Simvastatin promotes NPC1-mediated free cholesterol efflux from lysosomes through CYP7A1/LXRalpha signalling pathway in oxLDL-loaded macrophages. J. Cell Mol. Med. 21: 364-374.  https://doi.org/10.1111/jcmm.12970
  29. Pfisterer SG, Peranen J, Ikonen E. 2016. LDL-cholesterol transport to the endoplasmic reticulum: current concepts. Curr. Opin. Lipidol. 27: 282-287.  https://doi.org/10.1097/MOL.0000000000000292
  30. Vanier MT. 2015. Complex lipid trafficking in Niemann-Pick disease type C. J. Inherit. Metab. Dis. 38: 187-199.  https://doi.org/10.1007/s10545-014-9794-4
  31. Tall AR, Yvan-Charvet L. 2015. Cholesterol, inflammation and innate immunity. Nat. Rev. Immunol. 15: 104-116.  https://doi.org/10.1038/nri3793
  32. Zheng XX, Xu YL, Li SH, Liu XX, Hui R, Huang XH. 2011. Green tea intake lowers fasting serum total and LDL cholesterol in adults: a meta-analysis of 14 randomized controlled trials. Am. J. Clin. Nutr. 94: 601-610.  https://doi.org/10.3945/ajcn.110.010926
  33. Park JY, Shin HK, Lee YJ, Choi YW, Bae SS, Kim CD. 2009. The mechanism of vasorelaxation induced by Schisandra chinensis extract in rat thoracic aorta. J. Ethnopharmacol. 121: 69-73.  https://doi.org/10.1016/j.jep.2008.09.031
  34. Brown MS, Goldstein JL. 1984. How LDL receptors influence cholesterol and atherosclerosis. Sci. Am. 251: 58-66.  https://doi.org/10.1038/scientificamerican1184-58
  35. Sirinian MI, Belleudi F, Campagna F, Ceridono M, Garofalo T, Quagliarini F, et al. 2005. Adaptor protein ARH is recruited to the plasma membrane by low density lipoprotein (LDL) binding and modulates endocytosis of the LDL/LDL receptor complex in hepatocytes. J. Biol. Chem. 280: 38416-38423.  https://doi.org/10.1074/jbc.M504343200
  36. Ragusa R, Basta G, Neglia D, De Caterina R, Del Turco S, Caselli C. 2021. PCSK9 and atherosclerosis: looking beyond LDL regulation. Eur. J. Clin. Invest. 51: e13459. 
  37. Macchi C, Sirtori C, Corsini A, Santos R, Watts G, Ruscica M. 2019. A new dawn for managing dyslipidemias: the era of RNA-based therapies. Pharmacol. Res. 150: 104413. 
  38. Choi HK, Hwang JT, Nam TG, Kim SH, Min DK, Park SW, et al. 2017. Welsh onion extract inhibits PCSK9 expression contributing to the maintenance of the LDLR level under lipid depletion conditions of HepG2 cells. Food Funct. 8: 4582-4591.  https://doi.org/10.1039/C7FO00562H
  39. Choi HK, Kim HJ, Hwang JT, Chung MY. 2017. Allium tuberosum reverses PCSK9-mediated LDLR degradation by inhibition of HNF1α. J. Korean Soc. Food Sci. Nutr. 46: 1278-1285. 
  40. Wang F, Zhao C, Tian G, Wei X, Ma Z, Cui J, et al. 2020. Naringin alleviates atherosclerosis in ApoE(-/-) mice by regulating cholesterol metabolism involved in gut microbiota remodeling. J. Agric. Food Chem. 68: 12651-12660.  https://doi.org/10.1021/acs.jafc.0c05800
  41. Hwang JT, Kim HJ, Choi HK, Park JH, Chung S, Chung MY. 2020. Butein synergizes with statin to upregulate low-density lipoprotein receptor through HNF1alpha-mediated PCSK9 inhibition in HepG2 cells. J. Med. Food 23: 1102-1108.  https://doi.org/10.1089/jmf.2020.4761
  42. Cui CJ, Jin JL, Guo LN, Sun J, Wu NQ, Guo YL, et al. 2020. Beneficial impact of epigallocatechingallate on LDL-C through PCSK9/LDLR pathway by blocking HNF1alpha and activating FoxO3a. J. Transl. Med. 18: 1-13.  https://doi.org/10.1186/s12967-019-02189-8
  43. Jia Q, Cao H, Shen D, Li S, Yan L, Chen C, et al. 2019. Quercetin protects against atherosclerosis by regulating the expression of PCSK9, CD36, PPARgamma, LXRalpha and ABCA1. Int. J. Mol. Med. 44: 893-902.  https://doi.org/10.3892/ijmm.2019.4263
  44. Dong Z, Zhang W, Chen S, Liu C. 2019. Silibinin A decreases statininduced PCSK9 expression in human hepatoblastoma HepG2 cells. Mol. Med. Rep. 20: 1383-1392.  https://doi.org/10.3892/mmr.2019.10344
  45. Gao WY, Chen PY, Chen SF, Wu MJ, Chang HY, Yen JH. 2018. Pinostrobin inhibits proprotein convertase subtilisin/kexin-type 9 (PCSK9) gene expression through the modulation of FoxO3a protein in HepG2 cells. J. Agric. Food Chem. 66: 6083-6093.  https://doi.org/10.1021/acs.jafc.8b02559
  46. Razgonova M, Zakharenko A, Pikula K, Kim E, Chernyshev V, Ercisli S, et al. 2020. Rapid mass spectrometric study of a supercritical CO2-extract from woody liana Schisandra chinensis by HPLC-SPD-ESI-MS/MS. Molecules 25: 2689. 
  47. Kim Y, Kim E, Jeong G. 2019. Isolation and quantitative analysis of schisandrin, gomisin A and gomisin M2 from Schisandra chinensis. Korean J. Pharmacogn. 50: 148-153. 
  48. Choi YH. 2018. Schisandrin A prevents oxidative stress-induced DNA damage and apoptosis by attenuating ROS generation in C2C12 cells. Biomed. Pharmacother. 106: 902-909.  https://doi.org/10.1016/j.biopha.2018.07.035
  49. Fu K, Zhou H, Wang C, Gong L, Ma C, Zhang Y, et al. 2022. A review: pharmacology and pharmacokinetics of schisandrin A. Phytother. Res. 36: 2375-2393.  https://doi.org/10.1002/ptr.7456
  50. Kwon DH, Cha HJ, Choi EO, Leem SH, Kim GY, Moon SK, et al. 2018. Schisandrin A suppresses lipopolysaccharide-induced inflammation and oxidative stress in RAW 264.7 macrophages by suppressing the NF-κB, MAPKs and PI3K/Akt pathways and activating Nrf2/HO-1 signaling. Int. J. Mol. Med. 41: 264-274.  https://doi.org/10.3892/ijmm.2017.3209
  51. Jeong MJ, Kim SR, Jung UJ. 2019. Schizandrin A supplementation improves nonalcoholic fatty liver disease in mice fed a high-fat and high-cholesterol diet. Nutr. Res. 64: 64-71.  https://doi.org/10.1016/j.nutres.2019.01.001
  52. Sun JH, Liu X, Cong LX, Li H, Zhang CY, Chen JG, et al. 2017. Metabolomics study of the therapeutic mechanism of Schisandra chinensis lignans in diet-induced hyperlipidemia mice. Lipids Health Dis. 16: 145.