Journal of the East Asian Society of Dietary Life (동아시아식생활학회지)

The East Asian Society of Dietary Life (동아시아식생활학회)
권호 표지

Comparison of the Effects of Cyclodextrin-Naringin Inclusion Complex with Naringin on Lipid Metabolism in Mice Fed a High-Fat Diet

고지방식이를 섭취한 마우스에서 나린진과 나린진-사이클로텍스트린 포접화합물의 지질대사에 대한 영향 비교

  • Jeon, Seon-Min (Dept. of Food Science and Nutrition and Center for Food and Nutritional Genomics, Kyungpook National University) ;
  • Choi, Myung-Sook (Dept. of Food Science and Nutrition and Center for Food and Nutritional Genomics, Kyungpook National University)
  • 전선민 (경북대학교 식품영양학과 및 식품영양유전체연구센터) ;
  • 최명숙 (경북대학교 식품영양학과 및 식품영양유전체연구센터)
  • Received : 2009.12.02
  • Accepted : 2010.01.27
  • Published : 2010.02.28
Download PDF
⟨ Previous Next ⟩

Abstract

Naringin has antioxidant and antihyperlipidemic properties, however, phenolic compounds including naringin are unstable in the presence of light, heat and oxygen. Beta-cyclodextrin ($\beta$-CD) is a cyclic heptamer composed of seven glucose units that enhances the stability and solubility of molecules through the formation of inclusion complexes. This study was conducted out to compare the effects of CD-naringin (CD-N) inclusion complexes with naringin on lipid metabolism in high fat-fed animals. Male C57BL/6 mice were fed either CD-N (0.048%, w/w) or naringin (N, 0.02%, w/w) in a 20% high-fat (HFC, 15% lard, 5% corn oil, w/w) diet for 10 weeks. Orlistat (Xenical, 0.01%, w/w) was used as a positive control (PC). There were no differences in body weight, food intake, liver and heart weights, plasma triglyceride(TG), leptin, adiponectin, resistin, IL-$1{\beta}$ and IL-6 concentrations, and hepatic $\beta$-oxidation, carnitine palmitoyl transferase(CPT), glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme activities between the HFC and CD-N groups or between the HFC and N groups. However, both CD-naringin and naringin supplementation les to a significant reduction in the epididymal and perirenal white adipose tissue weights, plasma free fatty acid, insulin and blood glucose concentrations, hepatic cholesterol and TG contents and hepatic fatty acid synthase (FAS), phosphatidate phosphohydrolase (PAP) and HMG-CoA reductase activities compared to the HFC group. The plasma HDL-cholesterol concentration was significantly higher in CD-N and N groups than in HF and PC groups. These results indicate that both CD-naringin and naringin supplementation effectively improved plasma and hepatic lipid metabolism without differences between CD-N and naringin groups.

본 연구에서는 항고지혈, 항당뇨, 항동맥경화 등의 기능성이 잘 알려진 naringin을 이용하여 빛, 열, 산소 등의 산화환경을 개선시킴으로써 지질대사 개선에 대한 유용성이 증가되는지를 알아보고자 하였다. 즉, 불안정한 naringin 등의 flavonoid를 cyclodextrin 분자의 소수성 공동에 포접시켜 안정성을 증가시킴으로써 지질대사가 naringin 단독 보충에 비해 개선되는지를 분석하고, 이 연구 결과를 토대로 건강 기능식품에 적용 가능한지에 대한 여부를 검토하고자 하였다. 이에 20% 고지방식이에 0.02% naringin 및 naringin이 0.02% 첨가되도록 CD-naringin 량을 조절하여 10주간 C57BL/6 mice에 보충한 결과, 체중 및 식이 섭취량에는 차이가 없었으나, HFC 군에 비해 CD-N군 및 N군에서 백색지방 무게가 유의적으로 감소되었다. 뿐만 아니라, CD-N군 및 N군에서 혈장 총콜레스테롤, 유리지방산, 혈당 및 간 조직 콜레스테롤과 중성지방 농도가 HFC군에 비해 유의적으로 감소하였고, 혈장 HDL-콜레스테롤 농도는 유의적으로 증가하였다. 혈장 및 간조직 지질 농도는 간 조직 지질대사 관련 효소 활성도와 일치하는 경향을 보여주었는데, CD-naringin 및 naringin 보충은 지방산 산화 증가에는 효과가 없었으나, 간 조직 지방산, 중성지방 및 콜레스테롤 합성 억제에는 매우 효과적인 것으로 나타났다. 또한 지질대사 관련 호르몬 및 adipokine 농도 비교결과, 혈장 인슐린 농도는 CD-naringin 및 naringin 보충에 의해 유의 적으로 감소되었으나, leptin, adiponectin, resistin, IL-$1{\beta}$, IL-6 등은 유의적인 차이를 나타내지 않았다. 또한 췌장 lipase 억제제로서 비만 치료제로 이용되고 있는 orlistat에 비해 지질대사 개선 효과가 비슷하게 나타났으나, orlistat와는 다른 기전에 의한 지질대사 개선 효과로 보인다. 결론적으로, CD-naringin inclusion complex 및 naringin 단독 보충은 장기간의 고지방식이에 의한 지질대사 이상 및 인슐린 저항성 개선 효능을 기대해 볼 수 있으나, 혈장 leptin, resistin, IL-$1{\beta}$ 등의 염증성, 인슐린 저항성을 증가시키는 호르몬/adipokine 농도 감소 및 인슐린 저항성 개선 또는 항염증성 adipokine인 혈장 adiponectin 및 IL-6 농도 증가에 대한 효과는 나타나지 않는 것으로 판단되며, 두 물질의 효능 차이 또한 나타나지 않아 건강기능식품에 적용하기 위해서는 항산화 효과에 대한 CD-naringin의 유용성 연구가 필요할 것으로 판단된다.

Keywords

References

  1. Annuzzi G, Bozzetto L, Patti L, Santangelo C, Giacco R, Di Marino L, De Natale C, Masella R, Riccardi G, Rivellese AA (2009) Type 2 diabetes mellitus is characterized by reduced postprandial adiponectin response: a possible link with diabetic postprandial dyslipidemia. Metabolism Nov 17.
  2. Aylwin S, Al-Zaman Y (2008) Emerging concepts in the medical and surgical treatment of obesity. Front Horm Res 36: 229-259. https://doi.org/10.1159/000115368
  3. Bieber LL, Abraham T, Helmrath T (1972) A rapid spectrophotometric assay for camitine palmitoy1 transferase. Anal Biochem 50: 509-518. https://doi.org/10.1016/0003-2697(72)90061-9
  4. Borst SE, Conover CF (2005) High-fat diet induces increased tissue expression of TNF-alpha. Life Sci 77: 2156-2165. https://doi.org/10.1016/j.lfs.2005.03.021
  5. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 7: 248-254.
  6. Browne CD, Hindmarsh EJ, Smith JW (2006) Inhibition of endothelial cell proliferation and angiogenesis by orlistat, a fatty acid synthase inhibitor. FASEB J 20: 2027-2035. https://doi.org/10.1096/fj.05-5404com
  7. Carl MN, Lakshmanan MR, Porter JW (1975) Fatty acid synthase from rat liver. Methods Enzymol 35: 37-44. https://doi.org/10.1016/0076-6879(75)35136-7
  8. Choi MS, Lee MK, Jung UJ, Kim HJ, Do GM, Park YB, Jeon SM (2009) Metabolic response of soy pinitol on lipid-lowering, antioxidant and hepatoprotective action in hamsters fed-high fat and high cholesterol diet. Mol Nutr Food Res 53: 751-759. https://doi.org/10.1002/mnfr.200800241
  9. Czerwienska B, Kokot F, Franek E, Irzyniec T, Wiecek A (2004) Effect of orlistat therapy on carbohydrate, lipid, vitamin and hormone plasma levels in obese subjects. Pol Arch Med Wewn 112: 1415-1423.
  10. Dimitrov D, Bohchelian H, Koeva L (2005) Effect of orlistat on plasma leptin levels and risk factors for the metabolic syndrome. Metab Syndr Relat Disord 3: 122-129. https://doi.org/10.1089/met.2005.3.122
  11. Folch J, Lees M, Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226: 497-509.
  12. Fonseca VA (2008) Identification and treatment of prediabetes to prevent progression to type 2 diabetes. Clin Cornerstone 9: 51-59. https://doi.org/10.1016/S1098-3597(09)62039-1
  13. Glock GE, McLean P (1953) Further studies on the properties and assay of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase of rat liver. Biochem J 55: 400-408. https://doi.org/10.1042/bj0550400
  14. Hara K, Hashimoto H (1986) Application of cyclodextrin. J Jpn Soc Starch Sci 3: 151-161.
  15. Higashimoto M, Yamato H, Kinouchi T, Ohnishi Y (1998) Inhibitory effects of citrus fruits on the mutagenicity of l-methy1-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid treated with nitrite in the presence of ethanol. Mutat Res 415: 219-226. https://doi.org/10.1016/S1383-5718(98)00079-5
  16. Iglesias-Osma MC, Torres MA, Garcia-Barrado MJ, Moratinos J (2008) Adipocytokines: implications in the prognosis and drug treatment of cardiovascular diseases. Rev Clin Esp 208: 239-246. https://doi.org/10.1157/13119918
  17. Jeon SM (2001) Effects of naringin, vitamin E and cholesterol-lowering drugs on cholesterol and antioxidant metabolism and related gene expressio in rabbits fed high cholesterol diet. Ph D Dissertation Kyungpook Naional University. Daegu. pp 131-133.
  18. Jeon SM, Park YB, Choi MS (2004) Antihypercholesterolemic property of naringin alters plasma and tissue lipids, cholesterol-regulating enzymes, fecal sterol and tissue morphology in rabbits. Clin Nutr 23: 1025-1034. https://doi.org/10.1016/j.clnu.2004.01.006
  19. Jung UJ, Lee MK, Jeong KS, Choi MS (2004) The hypoglycemic effects of hesperidin and naringin are partly mediated by hepatic glucose-regulating enzymes in C57BL/KsJ-db/db mice. J Nutr 134: 2499-2503. https://doi.org/10.1093/jn/134.10.2499
  20. Jung UJ, Lee MK, Park YB, Kang MA, Choi MS (2006) Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mRNA levels in type-2 diabetic mice. Int J Biochem Cell BioI 38: 1134-1145. https://doi.org/10.1016/j.biocel.2005.12.002
  21. Kamihira M, Asai T, Yamagata Y, Taniguchi M, Kobayasi T (1990) Formation of inclusion complexes between cyclodextrins and aromatic compounds under pressurized carbon dioxide. J Ferment Bioeng 69: 350-353. https://doi.org/10.1016/0922-338X(90)90242-O
  22. Kaneko T, Nakamura T, Horikoshi K (1987) Spectrophotometiric determination of cylization activity of $\beta$-cyclodextrin forming cyclodextrin glucanotransferase. J Jpn Soc Starch Sci 24: 45-48.
  23. Kelley DE, Kuller LH, McKolanis TM, Harper P, Mancino J, Kalhan S (2004) Effects of moderate weight loss and orlistat on insulin resistance, regional adiposity, and fatty acids in type 2 diabetes. Diabetes Care 27: 33-40. https://doi.org/10.2337/diacare.27.1.33
  24. Kim DH, Jung EA, Shong IS, Han JA, Kim TH, Han MJ (1998) Intestinal bacterial metabolism of flavonoids and its relation to some biological activities. Arch Pharm Res 21: 17-23. https://doi.org/10.1007/BF03216747
  25. Kim HJ, Oh GT, Park YB, Lee MK, Seo HJ, Choi MS (2004) Naringin alters the cholesterol biosynthesis and antioxidant enzyme activities in LDL receptor-knockout mice under cholesterol fed condition. Life Sci 74: 1621-1634. https://doi.org/10.1016/j.lfs.2003.08.026
  26. Kim IS, Chae SC, Kim DW (2009) Effects of onion and naringin extract mixed products on antihyperlipidemic levels of bio FIB hamster. Korean J Microscopy 39: 191-197.
  27. Kim SY, Kim HJ, Lee MK, Jeon SM, Do GM, Kwon EY, Cho YY, Kim DJ, Jeong KS, Park YB, Ha TY, Choi MS (2006) Naringin time-dependently lowers hepatic cholesterol biosynthesis and plasma cholesterol in rats fed high-fat and high-cholesterol diet. J Med Food 9: 582-586. https://doi.org/10.1089/jmf.2006.9.582
  28. Kim TK, Shin HD, Lee YH (2003) Stabilization of polypheNolie antioxidants using inclusion complexation with cyClodextrin and their utilization as the fresh-food preservative. Korean J Food Sci Technol 35: 266-271.
  29. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen IT (2002) The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288: 2709-2716. https://doi.org/10.1001/jama.288.21.2709
  30. Lazarow PB (1981) Assay of peroxisomal beta-oxidation of fatty acids. Methods Enzymol 72: 315-319. https://doi.org/10.1016/S0076-6879(81)72021-4
  31. Le Marchand L, Murphy SP, Hankin JH, Wilkens LR. Kolonel LN (2000) Intake of flavonoids and lung cancer. J Natl Cancer Inst 92: 154-160. https://doi.org/10.1093/jnci/92.2.154
  32. Lu Z, Wang Z, Wang X, Diao B, Feng X, He F, Zou Q, Gan L (2009) Protection from high-fat-diet-induced impaired glucose tolerance in female Sprague-Dawley rats. Gynecol Endocrinol 25: 464-471. https://doi.org/10.1080/09513590902770107
  33. Luc G, Empana JP, Morange P, Juhan-Vague I, Arveiler D, Ferrieres J, Amouyel P, Evans A, Kee F, Bingham A, Machez E, Ducimetiere P (2009) Adipocytokines and the risk of coronary heart disease in healthy middle aged men: the PRIME study. Int JObes (Lond) Oct 13 [Epub ahead of print]
  34. Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y, Komuro R. Ouchi N, Kihara S, Tochino Y, Okutomi K, Horie M, Takeda S, Aoyama T, Funahashi T, Matsuzawa Y (2002) Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 8: 731-737. https://doi.org/10.1038/nm724
  35. Ochoa S (1995) Malic enzymeL malic enzymes from pigeon and wheat germ. In Methods in Enzymology (SP Colowick and NO Kaplan eds). Academic Press, New York, USA. pp 323-326.
  36. Pszczola DE (1998) Production and potential food application of cyclodextrins. Food Tech 42: 96-100.
  37. Shapiro DJ, Nordstrom JL, Mitschelen JJ, Rodwell VW, Schimke RT (1974) Micro assay for 3-hydroxy-3-methylglutaryl-CoA reductase in rat liver and in L-cell fibroblasts. Biochim Biophys Acta 370: 369-377. https://doi.org/10.1016/0005-2744(74)90098-9
  38. Shin YW, Bok SH, Jeong TS, Bae KH, Jeoung NH, Choi MS, Lee SH, Park YB (1999) Hypocholesterolemic effect of naringin associated with hepatic cholesterol regulating enzyme changes in rats. Int J Vitam Nutr Res 69: 341-347. https://doi.org/10.1024/0300-9831.69.5.341
  39. Song SH, Lee HJ, Chang SJ, Woo GJ (1993) Microencapsulation of garlic oil with $\beta$-cyclodextrin. Foods and Biotechnol 2: 132-135.
  40. Tsai SH, Lin-Shiau SY, Lin JK (1999) Suppression of nitric oxide synthase and the down-regulation of the activation of NFkappaB in macrophages by resveratrol. Br J Pharmacol 125: 673-680.
  41. Walton PA, Possmayer F (1985) $Mg_2$-dependent phosphatidate phosphohydrolase of rat lung: development of an assay employing a defined chemical substrate which reflects the phosphohydrolase activity measured using membrane-bound substrate. Anal Biochem 151: 479-486. https://doi.org/10.1016/0003-2697(85)90208-8
  42. Yamajaki K, Murat M (1990) Frequency of atherogenic risk factors in Japanese obese children. Diabetes Res Clin Pract 10: S211-S219. https://doi.org/10.1016/0168-8227(90)90166-Q