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Increased effects of ginsenosides on the expression of cholesterol 7α-hydroxylase but not the bile salt export pump are involved in cholesterol metabolism

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Abstract

An extract from red ginseng [steamed and dried roots of Panax ginseng C.A. Meyer (RGE)] has been shown to have various actions on physiological functions. The mechanisms by which RGE promotes cholesterol metabolism in the liver are unclear, but RGE decreases the plasma levels of cholesterol. We investigated whether RGE affected the mRNA expression of cholesterol metabolism-related proteins such as cytochrome P450 (CYP)7A1 and bile salt export pump (BSEP) in the liver in hypercholesterolemic rats and rat primary hepatocytes. In-vivo studies showed the upregulation of CYP7A1 mRNA in hypercholesterolemic rats treated with RGE. Treatment with RGE exhibited decreased ratios of low-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol compared with hypercholesterolemia without RGE. In-vitro studies also showed the upregulation of CYP7A1 mRNA and protein levels by the addition of RGE to rat primary hepatocytes. The mRNA levels of BSEP exhibited few changes. The sustained levels of the liver X receptor (LXR) in vivo and the increased levels of LXR in vitro on RGE treatment could be involved in the upregulation of CYP7A1. To clarify the effects of 11 ginsenosides including RGE on the mRNA levels of CYP7A1 and BSEP, we performed in-vitro experiments using rat primary hepatocytes. The ginsenosides Ro, Rg3, Re, Rg1, and Rg2 exhibited increased mRNA levels of CYP7A1. These results suggest that several ginsenosides including RGE promoted cholesterol metabolism due to upregulation of CYP7A1.

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References

  1. Yamamoto M, Kumagai A, Yamamura Y (1983) Plasma lipid-lowering action of ginseng saponins and mechanism of the action. Am J Chin Med 11:84–87

    Article  PubMed  CAS  Google Scholar 

  2. Cui X, Sakaguchi T, Ishizuka D, Tsukada K, Hatakeyama K (1998) Orally administered ginseng extract reduces serum total cholesterol and triglycerides that induce fatty liver in 66 % hepatectomized rats. J Int Med Res 26:181–187

    PubMed  CAS  Google Scholar 

  3. Kim SH, Park KS (2003) Effects of Panax ginseng extract on lipid metabolism in humans. Pharmacol Res 48:511–513

    Article  PubMed  CAS  Google Scholar 

  4. Ji W, Gong BQ (2007) Hypolipidemic effects and mechanisms of Panax notoginseng on lipid profile in hyperlipidemic rats. J Ethnopharmacol 113:318–324

    Article  PubMed  CAS  Google Scholar 

  5. Hwang SY, Son DJ, Kim IW, Kim DM, Sohn SH, Lee JJ, Kim SK (2008) Korean red ginseng attenuates hypercholesterolemia-enhanced platelet aggregation through suppression of diacylglycerol liberation in high-cholesterol-diet-fed rabbits. Phytother Res 22:778–783

    Article  PubMed  CAS  Google Scholar 

  6. Song YB, An YR, Kim SJ, Park HW, Jung JW, Kyung JS, Hwang SY, Kim YS (2012) Lipid metabolic effect of Korean red ginseng extract in mice fed on a high-fat diet. J Sci Food Agric 92:388–396

    Article  PubMed  CAS  Google Scholar 

  7. Fernandez C, Lobo MV, Gomez-Coronado D, Lasuncion MA (2004) Cholesterol is essential for mitosis progression and its deficiency induces polyploidy cell formation. Exp Cell Res 300:109–120

    Article  PubMed  CAS  Google Scholar 

  8. Fernandez C, Martin M, Gomez-Coronado D, Lasuncion MA (2005) Effects of distal cholesterol biosynthesis inhibitors on cell proliferation and cell cycle progression. J Lipid Res 46:920–929

    Article  PubMed  CAS  Google Scholar 

  9. Imamura T, Doi Y, Arima H, Yonemoto K, Hata J, Kubo M, Tanizaki Y, Ibayashi S, Iida M, Kiyohara Y (2009) LDL cholesterol and the development of stroke subtypes and coronary heart disease in a general Japanese population: the Hisayama study. Stroke 40:382–388

    Article  PubMed  CAS  Google Scholar 

  10. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366:1267–1278

    Article  PubMed  CAS  Google Scholar 

  11. Marti-Fabregas J, Gomis M, Arboix A, Aleu A, Pagonabarraga J, Belvis R, Cocho D, Roguer J, Rodriguez A, Garcia MD, Molina-Porcel L, Diaz-Manera J, MartiVilalta JL (2004) Favorable outcome of ischemic stroke in patients pretreated with statins. Stroke 35:1117–1121

    Article  PubMed  CAS  Google Scholar 

  12. Elkind MS, Flint AC, Sciacca RR, Sacco RL (2005) Lipid-lowering agent use at ischemic stroke onset is associated with decreased mortality. Neurology 65:253–258

    Article  PubMed  CAS  Google Scholar 

  13. Myant NB, Mitropoulos KA (1977) Cholesterol 7 alpha-hydroxylase. J Lipid Res 18:135–153

    PubMed  CAS  Google Scholar 

  14. Jelinek DF, Andersson S, Slaughter CA, Russell DW (1990) Cloning and regulation of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis. J Biol Chem 265:8190–8197

    PubMed  CAS  Google Scholar 

  15. Redinger RN (2003) The coming of age of our understanding of the enterohepatic circulation of bile salts. Am J Surg 185:168–172

    Article  PubMed  CAS  Google Scholar 

  16. Jansen PL, Strautnieks SS, Jacquemin E, Hadchouel M, Sokal EM, Hooiveld GJ, Koning JH, De Jager-Krikken A, Kuipers F, Stellaard F, Bijleveld CM, Gouw A, Van Goor H, Thompson RJ, Muller M (1999) Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology 117:1370–1379

    Article  PubMed  CAS  Google Scholar 

  17. Akita H, Suzuki H, Ito K, Kinoshita S, Sato N, Takikawa H, Sugiyama Y (2001) Characterization of bile acid transport mediated by multidrug resistance associated protein 2 and bile salt export pump. Biochim Biophys Acta 1511:7–16

    Article  PubMed  CAS  Google Scholar 

  18. Honkakoski P, Zelko I, Sueyoshi T, Negishi M (1998) The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol Cell Biol 18:5652–5658

    PubMed  CAS  Google Scholar 

  19. Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterstrom RH, Perlmann T, Lehmann JM (1998) An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92:73–82

    Article  PubMed  CAS  Google Scholar 

  20. Waxman DJ (1999) P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch Biochem Biophys 369:11–23

    Article  PubMed  CAS  Google Scholar 

  21. Niesor EJ, Flach J, Lopes-Antoni I, Perez A, Bentzen CL (2001) The nuclear receptors FXR and LXRalpha: potential targets for the development of drugs affecting lipid metabolism and neoplastic diseases. Curr Pharm Des 7:231–259

    Article  PubMed  CAS  Google Scholar 

  22. Chiang JY, Kimmel R, Stroup D (2001) Regulation of cholesterol 7 alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha). Gene 262:257–265

    Article  PubMed  CAS  Google Scholar 

  23. Wang J, Einarsson C, Murphy C, Parini P, Bjorkhem I, Gafvels M, Eggertsen G (2006) Studies on LXR-and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice. J Lipid Res 47:421–430

    Article  PubMed  CAS  Google Scholar 

  24. Kitagawa I, Yoshikawa M, Yoshihara M, Hayashi T, Taniyama T (1983) Chemical studies on crude drug precession. I. On the constituents of Ginseng Radix Rubra. Yakugaku Zasshi 103:612–622

    PubMed  CAS  Google Scholar 

  25. Samukawa K, Yamashita H, Matsuda H, Kubo M (1995) Simultaneous analysis of saponins in Ginseng Radix by high performance liquid chromatography. Chem Pharm Bull 43:137–141

    Article  CAS  Google Scholar 

  26. Samukawa K, Yamashita H, Matsuda H, Kubo M (1995) Simultaneous analysis of ginsenosides of various Ginseng Radix by HPLC. Yakugaku Zasshi 115:241–249

    PubMed  CAS  Google Scholar 

  27. Seglen PO (1976) Preparation of isolated rat liver cells. Methods Cell Biol 13:29–83

    Article  PubMed  CAS  Google Scholar 

  28. Kawase A, Fujii A, Negoro M, Akai R, Ishikubo M, Komura H, Iwaki M (2008) Differences in cytochrome P450 and nuclear receptor mRNA levels in liver and small intestine between SD and DA rats. Drug Metab Pharmacokinet 23:196–206

    Article  PubMed  CAS  Google Scholar 

  29. Pullinger CR, Eng C, Salen G, Shefer S, Batta AK, Erickson SK, Verhagen A, Rivera CR, Mulvihill SJ, Malloy MJ, Kane JP (2002) Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J Clin Invest 110:109–117

    PubMed  CAS  Google Scholar 

  30. Del Bas JM, Fernandez-Larrea J, Blay M, Ardevol A, Salvado MJ, Arola L, Blade C (2005) Grape seed procyanidins improve atherosclerotic risk index and induce liver CYP7A1 and SHP expression in healthy rats. FASEB J 19:479–481

    PubMed  Google Scholar 

  31. Yamamoto M, Uemura T, Nakama S, Uemiya M, Kumagai A (1983) Serum HDL-cholesterol-increasing and fatty liver-improving actions of Panax ginseng in high cholesterol diet-fed rats with clinical effect on hyperlipidemia in man. Am J Chin Med 11:96–101

    Article  PubMed  CAS  Google Scholar 

  32. Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ (1998) Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 93:693–704

    Article  PubMed  CAS  Google Scholar 

  33. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD, Shan B (2000) Role of LXRs in control of lipogenesis. Genes Dev 14:2831–2838

    Article  PubMed  CAS  Google Scholar 

  34. Gupta S, Pandak WM, Hylemon PB (2002) LXR alpha is the dominant regulator of CYP7A1 transcription. Biochem Biophys Res Commun 293:338–343

    Article  PubMed  CAS  Google Scholar 

  35. Maglich JM, Stoltz CM, Goodwin B, Hawkins-Brown D, Moore JT, Kliewer SA (2002) Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol 62:638–646

    Article  PubMed  CAS  Google Scholar 

  36. Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ (2000) Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102:731–744

    Article  PubMed  CAS  Google Scholar 

  37. Ananthanarayanan M, Balsubramanian N, Makishima M, Mangelsdorf DJ (2001) Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem 276:28857–28865

    Article  PubMed  CAS  Google Scholar 

  38. Plass JR, Mol O, Heegsma J, Geuken M, Faber KN, Jansen PL, Muller M (2002) Farnesoid X receptor and bile salts are involved in transcriptional regulation of the gene encoding the human bile salt export pump. Hepatology 35:589–596

    Article  PubMed  CAS  Google Scholar 

  39. Brown MS, Goldstein JL (1997) The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89:331–340

    Article  PubMed  CAS  Google Scholar 

  40. Horton JD, Shimomura I, Brown MS, Hammer RE, Goldstein JL, Shimano H (1998) Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2. J Clin Invest 101:2331–2339

    Article  PubMed  CAS  Google Scholar 

  41. Shimano H, Horton JD, Hammer RE, Shimomura I, Brown MS, Goldstein JL (1996) Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J Clin Invest 98:1575–1584

    Article  PubMed  CAS  Google Scholar 

  42. Inagaki T, Lin VY, Goetz R, Mohammadi M, Mangelsdorf DJ, Kliewer SA (2008) Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab 8:77–83

    Article  PubMed  CAS  Google Scholar 

  43. Quan LH, Min JW, Yang DU, Kim YJ, Yang DC (2012) Enzymatic biotransformation of ginsenoside Rb1 to 20(S)-Rg3 by recombinant β-glucosidase from Microbacterium esteraromaticum. Appl Microbiol Biotechnol 94:377–384

    Article  PubMed  CAS  Google Scholar 

  44. Hasegawa H, Sung JH, Matsumiya S, Uchiyama M (1996) Main ginseng saponin metabolites formed by intestinal bacteria. Planta Med 62:453–457

    Article  PubMed  CAS  Google Scholar 

  45. Akao T, Kida H, Kanaoka M, Hattori M, Kobashi K (1998) Intestinal bacterial hydrolysis is required for the appearance of compound K in rat plasma after oral administration of ginsenoside Rb1 from Panax ginseng. J Pharma Pharmacol 50:1155–1160

    Article  CAS  Google Scholar 

  46. Wakabayashi C, Murakami K, Hasegawa H, Murata J, Saiki I (1998) An intestinal bacterial metabolite of ginseng protopanaxadiol saponins has the ability to induce apoptosis in tumor cells. Biochem Biophys Res Commun 246:725–730

    Article  PubMed  CAS  Google Scholar 

  47. Bae EA, Park SY, Kim DH (2000) Constitutive beta-glucosidases hydrolyzing ginsenoside Rb1 and Rb2 from human intestinal bacteria. Biol Pharm Bull 23:1481–1485

    Article  PubMed  CAS  Google Scholar 

  48. Tawab MA, Bahr U, Karas M, Wurglics M, Schubert-Zsilavecz M (2003) Degradation of ginsenosides in humans after oral administration. Drug Metab Dispos 31:1065–1071

    Article  PubMed  Google Scholar 

  49. Hasegawa H, Uchiyama M (1998) Antimetastatic efficacy of orally administered ginsenoside Rb1 in dependence on intestinal bacterial hydrolyzing potential and significance of treatment with an active bacterial metabolite. Planta Med 64:696–700

    Article  PubMed  CAS  Google Scholar 

  50. Lee SJ, Ko WG, Kim JH, Sung JH, Moon CK, Lee BH (2000) Induction of apoptosis by a novel intestinal metabolite of ginseng saponin via cytochrome c-mediated activation of caspase-3 protease. Biochem Pharmacol 60:677–685

    Article  PubMed  CAS  Google Scholar 

  51. Bae EA, Choo MK, Park EK, Park SY, Shin HY, Kim DH (2002) Metabolism of ginsenoside Rc by human intestinal bacteria and its related antiallergic activity. Biol Pharm Bull 25:743–747

    Article  PubMed  CAS  Google Scholar 

  52. Choo MK, Park EK, Han MJ, Kim DH (2003) Antiallergic activity of ginseng and its ginsenosides. Planta Med 69:518–522

    Article  PubMed  CAS  Google Scholar 

  53. Xie HT, Wang GJ, Chen M, Jiang XL, Li H, Lv H, Huang CR, Wang R, Roberts M (2005) Uptake and metabolism of ginsenoside Rh2 and its aglycon protopanaxadiol by Caco-2 cells. Biol Pharm Bull 28:383–386

    Article  PubMed  CAS  Google Scholar 

  54. Han M, Fang XL (2006) Difference in oral absorption of ginsenoside Rg1 between in vitro and in vivo models. Acta Pharmacol Sin 27:499–505

    Article  PubMed  CAS  Google Scholar 

  55. Han M, Sha X, Wu Y, Fang X (2006) Oral absorption of ginsenoside Rb1 using in vitro and in vivo models. Planta Med 72:398–404

    Article  PubMed  CAS  Google Scholar 

  56. Xiong J, Sun M, Guo J, Huang L, Wang S, Meng B, Ping Q (2009) Active absorption of ginsenoside Rg1 in vitro and in vivo: the role of sodium-dependent glucose co-transporter 1. J Pharm Pharmacol 61:381–386

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Faculty of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka, 577-8502, Japan

    Atsushi Kawase, Ayano Yamada, Yuko Gamou, Chika Tahara, Kazuya Murata, Hideaki Matsuda & Masahiro Iwaki

  2. Research and Development Division, OHKI Group, 3-3 Kandakaji-cho, Chiyoda-ku, Tokyo, 101-0045, Japan

    Fumiaki Takeshita

  3. Department of Pharmacology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan

    Keiichi Samukawa

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  1. Atsushi Kawase
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  2. Ayano Yamada
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Correspondence to Masahiro Iwaki.

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Kawase, A., Yamada, A., Gamou, Y. et al. Increased effects of ginsenosides on the expression of cholesterol 7α-hydroxylase but not the bile salt export pump are involved in cholesterol metabolism. J Nat Med 67, 545–553 (2013). https://doi.org/10.1007/s11418-012-0713-4

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