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Inhibitory Effects of Functional Sujeonggwa Drinks on Hepatic Lipid Accumulation in Hypercholesterolemic ApoE Knockout Mice

고콜레스테롤혈증 ApoE Knockout Mice에서 기능성 수정과의 간지질 축적 억제 효과

  • Baek, Aran (Department of Food Science and Nutrition & Kimchi Research Institute, Pusan National University) ;
  • Kim, Mijeong (Department of Food Science and Nutrition & Kimchi Research Institute, Pusan National University) ;
  • Jung, Koeun (Department of Food Science and Nutrition & Kimchi Research Institute, Pusan National University) ;
  • Kim, Seulki (Department of Food Science and Nutrition & Kimchi Research Institute, Pusan National University) ;
  • Lee, Jeehyun (Department of Food Science and Nutrition & Kimchi Research Institute, Pusan National University) ;
  • Song, Yeong Ok (Department of Food Science and Nutrition & Kimchi Research Institute, Pusan National University)
  • 백아란 (부산대학교 식품영양학과 및 김치연구소) ;
  • 김미정 (부산대학교 식품영양학과 및 김치연구소) ;
  • 정고운 (부산대학교 식품영양학과 및 김치연구소) ;
  • 김슬기 (부산대학교 식품영양학과 및 김치연구소) ;
  • 이지현 (부산대학교 식품영양학과 및 김치연구소) ;
  • 송영옥 (부산대학교 식품영양학과 및 김치연구소)
  • Received : 2014.07.01
  • Accepted : 2014.07.17
  • Published : 2014.11.30

Abstract

In this study, the hepatic lipid-lowering effects and related mechanism of action of sujeonggwa were examined in hypercholesterolemia-induced apoprotein E knockout (apo E ko) mice. Sujeonggwa drink was prepared with cinnamon, ginger, and sugar by modifying the traditional recipe of sujeonggwa. Sugar was partially substituted with either stevia or short chain fructooligosaccharide (scFOS) in order to reduce the calorie content of sujeonggwa, which was measured by descriptive analysis. Apo E ko mice (n=42) were induced to have hypercholesterolemia (plasma total cholesterol concentration >1,000 mg/dL) by administration of a high cholesterol diet for 4 weeks, followed by division into six groups. Experimental groups were orally administered water as a vehicle (normal group), sugar solution (control group), commercially available 'V' sujeonggwa drink (positive control group), or three different types of sujeonggwa drinks (S-sugar, S-stevia, and S-scFOS group) for 6 weeks while high cholesterol diet was provided to all animals. Compared to the control group, concentrations of hepatic triglycerides, total cholesterol, thiobarbituric acid reactive substances, and reactive oxygen species in S-sugar, S-stevia, S-scFOS were significantly reduced (P<0.05), indicating that sujeonggwa had inhibitory effects on hepatic lipid accumulation. Protein expression levels of fatty acid synthase (FAS) and its transcription factor, sterol regulatory element-binding protein (SREBP)-1 responsible for triglyceride synthesis, as well as 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and its transcription factor, SREBP-2 responsible for cholesterol synthesis, were also reduced in S-sugar, S-stevia, and S-scFOS groups (P<0.05). These benefits of sujeonggwa were even greater in S-stevia and S-scFOS compared to S-sugar. The beneficial effects of S-stevia on regulation of hepatic lipid metabolism were slightly greater than those of S-scFOS although the differences were not significant. In conclusion, sujeonggwa drinks, especially functional sujeonggwa drinks in which sugar was partially substituted with stevia or scFOS, inhibited hepatic lipid accumulation via suppressing FAS and HMGCR protein expression through down-regulation of SREBP-1 and 2.

기능성 수정과의 대량생산을 위하여 전통 수정과로부터 계피, 생강 및 설탕을 사용하는 수정과 레시피를 개발하고, 감미료인 stevia와 scFOS를 첨가하여 기능성 수정과 레시피를 개발하였다. 수정과 레시피 개발은 수정과의 특성에 대해 전문 교육을 받은 관능 평가원 10명(총 50회)이 참여하였다. 수정과와 기능성 수정과의 간지질 축적 억제 효과 및 관련 기전 연구를 위해 유전적으로 변형된 마우스에서 4주간 콜레스테롤 식이로 고콜레스테롤혈증(총 콜레스테롤 >1,000 mg/dL)을 유발한 후 6주간 수정과를 경구로 섭취시켰다. 수정과 섭취량은 한국인의 1일 음료 섭취량을 기준으로 산출하였다. 간의 중성지방 및 콜레스테롤 농도는 설탕물을 섭취한 대조군에서 물을 섭취한 정상대조군에 비해 31.4%, 21.2% 유의적으로 증가하였으며(P<0.05) 동일한 농도의 설탕을 함유한 수정과 섭취에 의해 중성지방 17.9%(P=0.044) 그리고 콜레스테롤 12.6%(P=0.027) 감소하여 수정과의 지질 저하 효과를 확인하였고, 이러한 수정과의 효과는 설탕 함량의 일부를 stevia와 scFOS로 대체한 기능성 수정과군에서 더욱 낮았다. 그러나 시판 수정과의 간지질 농도는 설탕물만 섭취한 대조군과 유사하여 지질 축적 억제 효과가 관찰되지 않았는데, 이는 낮은 생강, 계피 추출물의 양 때문으로 생각되었다. 수정과군들의 FAS, HMGCR 및 SREBP-1, 2의 단백질 발현은 대조군에 비해 유의적으로 낮았으며 특히 기능성 수정과의 효과가 매우 높았다. 이상의 결과를 살펴보면 수정과의 기능성은 계피, 생강 및 당 함량의 모든 요인이 함께 작용한 것으로 확인되었다. 동일 농도의 설탕을 사용하였을 때 계피 및 생강의 효과는 유의적이었으며, 계피와 생강의 농도를 동일하게 하고 설탕 함량의 일부를 stevia와 scFOS로 대체한 기능성 수정과의 효과는 설탕만 사용한 수정과에 비해 유의적인 차이는 없었으나 간지질 축적 및 관련 효소 및 전사인자의 발현을 억제하는 효과가 매우 높았다.

Keywords

References

  1. Qin B, Polansky MM, Anderson RA. 2010. Cinnamon extract regulates plasma levels of adipose-derived factors and expression of multiple genes related to carbohydrate metabolism and lipogenesis in adipose tissue of fructose-fed rats. Horm Metab Res 42: 187-193. https://doi.org/10.1055/s-0029-1242746
  2. Kannappan S, Jayaraman T, Rajasekar P, Ravichandran MK, Anuradha CV. 2006. Cinnamon bark extract improves glucose metabolism and lipid profile in the fructose-fed rat. Singapore Med J 47: 858-863.
  3. Sheng X, Zhang Y, Gong Z, Huang C, Zang YQ. 2008. Improved insulin resistance and lipid metabolism by cinnamon extract through activation of peroxisome proliferatoractivated receptors. PPAR Res 2008: 581348.
  4. Lee JS, Jeon SM, Park EM, Huh TL, Kwon OS, Lee MK, Choi MS. 2003. Cinnamate supplementation enhances hepatic lipid metabolism and antioxidant defense systems in high cholesterol-fed rats. J Med Food 6: 183-191. https://doi.org/10.1089/10966200360716599
  5. Huang B, Yuan HD, Kim DY, Quan HY, Chung SH. 2011. Cinnamaldehyde prevents adipocyte differentiation and adipogenesis via regulation of peroxisome proliferator-activated receptor-${\gamma}$ ($PPAR{\gamma}$) and AMP-activated protein kinase (AMPK) pathways. J Agric Food Chem 59: 3666-3673. https://doi.org/10.1021/jf104814t
  6. Subash Babu P, Prabuseenivasan S, Ignacimuthu S. 2007. Cinnamaldehyde-a potential antidiabetic agent. Phytomedicine 14: 15-22.
  7. Gao H, Guan T, Li C, Zuo G, Yamahara J, Wang J, Li Y. 2012. Treatment with ginger ameliorates fructose-induced fatty liver and hypertriglyceridemia in rats: modulating of the hepatic carbohydrate response element-binding proteinmediated pathway. J Evidence-Based Complementary Altern Med 2012: 1-12.
  8. Nammi S, Kim MS, Gavande NS, Li GQ, Roufogalis BD. 2010. Regulation of low-density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase expression by Zingiber officinale in the liver of high-fat diet-fed rats. Basic Clin Pharmacol Toxicol 106: 389-395.
  9. Verma SK, Singh M, Jain P, Bordia A. 2004. Protective effect of ginger, Zingiber officinale Rosc on experimental atherosclerosis in rabbits. Indian J Exp Biol 42: 736-738.
  10. Thomson M, Al-Qattan KK, Al-Sawan SM, Alnaqeeb MA, Khan I, Ali M. 2002. The use of ginger (Zingiber officinale Rosc.) as a potential anti-inflammatory and antithrombotic agent. Prostaglandins Leukot Essent Fatty Acids 67: 475-478. https://doi.org/10.1054/plef.2002.0441
  11. El-Baroty GS, El-Baky HHA, Farag RS, Saleh MA. 2010. Characterization of antioxidant and antimicrobial compounds of cinnamon and ginger essential oils. Afr J Biochem Res 4: 167-174.
  12. Ahmed RS, Seth V, Banerjee BD. 2000. Influence of dietary ginger (Zingiber officinales Rosc) on antioxidant defense system in rat: comparison with ascorbic acid. Indian J Exp Biol 38: 604-606.
  13. Jiang X, Blair EY, McLachlan AJ. 2006. Investigation of the effects of herbal medicines on warfarin response in healthy subjects: a population pharmacokinetic-pharmacodynamic modelling approach. J Clin Pharmacol 46: 1370-1378. https://doi.org/10.1177/0091270006292124
  14. Nicoll R, Henein MY. 2009. Ginger (Zingiber officinale Roscoe): a hot remedy for cardiovascular disease? Int J Cardiol 131: 408-409. https://doi.org/10.1016/j.ijcard.2007.07.107
  15. Fuhrman B, Rosenblat M, Hayek T, Coleman R, Aviram M. 2000. Ginger extract consumption reduces plasma cholesterol, inhibits LDL oxidation and attenuates development of atherosclerosis in atherosclerotic, apolipoprotein E-deficient mice. J Nutr 130: 1124-1131.
  16. Dugasani S, Pichika MR, Nadarajah VD, Balijepalli MK, Tandra S, Korlakunta JN. 2010. Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol. J Ethnopharmacol 127: 515-520. https://doi.org/10.1016/j.jep.2009.10.004
  17. Choudhury D, Das A, Bhattacharya A, Chakrabarti G. 2010. Aqueous extract of ginger shows antiproliferative activity through disruption of microtubule network of cancer cells. Food Chem Toxicol 48: 2872-2880. https://doi.org/10.1016/j.fct.2010.07.020
  18. Park JE, Cha YS. 2010. Stevia rebaudiana Bertoni extract supplementation improves lipid and carnitine profiles in C57BL/6J mice fed a high-fat diet. J Sci Food Agric 90: 1099-1105. https://doi.org/10.1002/jsfa.3906
  19. Geeraert B, Crombe F, Hulsmans M, Benhabiles N, Geuns JM, Holvoet P. 2010. Stevioside inhibits atherosclerosis by improving insulin signaling and antioxidant defense in obese insulin-resistant mice. Int J Obes 34: 569-577. https://doi.org/10.1038/ijo.2009.261
  20. Cho BO, Ryu HW, So Y, Cho JK, Woo HS, Jin CH, Seo KI, Park JC, Jeong IY. 2013. Anti-inflammatory effect of austroinulin and 6-O-acetyl-austroinulin from Stevia rebaudiana in lipopolysaccharide-stimulated RAW264.7 macrophages. Food Chem Toxicol 62: 638-644. https://doi.org/10.1016/j.fct.2013.09.011
  21. Bornet FRJ, Brouns F, Tashiro Y, Duvillier V. 2002. Nutritional aspects of short-chain fructooligosaccharides: natural occurrence, chemistry, physiology and health implications. Dig Liver Dis 34: S111-S120. https://doi.org/10.1016/S1590-8658(02)80177-3
  22. Bouhnik Y, Achour L, Paineau D, Riottot M, Attar A, Bornet F. 2007. Four-week short chain fructo-oligosaccharides ingestion leads to increasing fecal bifidobacteria and cholesterol excretion in healthy elderly volunteers. Nutr J 6: 42. https://doi.org/10.1186/1475-2891-6-42
  23. Agheli N, Kabir M, Berni-Canani S, Petitjean E, Boussairi A, Luo J, Bornet F, Slama G, Rizkalla SW. 1998. Plasma lipids and fatty acid synthase activity are regulated by shortchain fructo-oligosaccharides in sucrose-fed insulin-resistant rats. J Nutr 128: 1283-1288.
  24. Tokunaga T, Oku T, Hosoya N. 1986. Influence of chronic intake of new sweetener fructooligosaccharide (neosugar) on growth and gastrointestinal function of the rat. J Nutr Sci Vitaminol 32: 111-121. https://doi.org/10.3177/jnsv.32.111
  25. Bush RS, Milligan LP. 1971. Study of the mechanism of inhibition of ketogenesis by propionate in bovine liver. Can J Anim Sci 51: 121-127. https://doi.org/10.4141/cjas71-016
  26. Baird GD, Lomax MA, Symonds HW, Shaw SR. 1984. Net hepatic and splanchnic metabolism of lactate, pyruvate and propionate in dairy cow in vivo in relation to lactation and nutrient supply. Biochem J 186: 47-57.
  27. Seo JH, Sung TH, Kim MR. 2002. Quality characteristics of Sujongkwa. J East Asian Soc Dietary Life 12: 370-378.
  28. Kusunoki J, Hansoty DK, Aragane K, Fallon JT, Badimon JJ, Fisher EA. 2001. Acyl-CoA: cholesterol acyltransferase inhibition reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 103: 2604-2609. https://doi.org/10.1161/01.CIR.103.21.2604
  29. Folch J, Lees M, Sloane Stanley GH. 1957. A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226: 497-509.
  30. Souza GA, Ebaid GX, Seiva FR, Rocha KH, Galhardi CM, Mani F, Novelli EL. 2011. N-acetylcysteine an allium plant compound improves high-sucrose diet-induced obesity and related effects. Evid Based Complement Alternat Med 2011: 643269.
  31. Sudhahar V, Kumar SA, Mythili Y, Varalakshmi P. 2007. Remedial effect of lupeol and its ester derivative on hypercholesterolemia-induced oxidative and inflammatory stresses. Nutr Res 27: 778-787. https://doi.org/10.1016/j.nutres.2007.09.012
  32. Monetti M, Levin MC, Watt MJ, Sajan MP, Marmor S, Hubbard BK, Stevens RD, Bain JR, Newgard CB, Farese RV Sr, Hevener AL, Farese RV Jr. 2007. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab 6: 69-78. https://doi.org/10.1016/j.cmet.2007.05.005
  33. Mancini-Filho J, Van-Koiij A, Mancini DA, Cozzolino FF, Torres RP. 1998. Antioxidant activity of cinnamon (Cinnamomum Zeylanicum, Breyne) extracts. Boll Chim Farm 137: 443-447.
  34. 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 https://doi.org/10.1172/JCI118951
  35. Okamoto M, Irii H, Tahara Y, Ishii H, Hirao A, Udagawa H, Hiramoto M, Yasuda K, Takanishi A, Shibata S, Shimizu I. 2011. Synthesis of a new [6]-gingerol analogue and its protective effect with respect to the development of metabolic syndrome in mice fed a high-fat diet. J Med Chem 54: 6295-6304. https://doi.org/10.1021/jm200662c
  36. Cherng S, Young J, Ma H. 2008. HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase) (HMGR). J Am Sci 4: 62-64.
  37. Rodwell VW, Nordstrom JL, Mitschelen JJ. 1976. Regulation of HMG-CoA reductase. Adv Lipid Res 14: 1-74. https://doi.org/10.1016/B978-0-12-024914-5.50008-5