Korean Journal of Clinical Laboratory Science (대한임상검사과학회지)

Korean Society for Clinical Laboratory Science (대한임상검사과학회)
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Protective Effects of Curcumin on CCl4-Induced Hepatic Fibrosis with High Fat Diet in C57BL/6 Mice

C57BL/6 마우스에서 고지방 식이와 CCl4로 유발한 간섬유증에 미치는 커큐민의 보호효과

  • Jekal, Seung-Joo (Department of Clinical Laboratory Science, Wonkwang Health Science University) ;
  • Min, Byung Woon (Department of Biomedical Laboratory Science, Hanlyeo University) ;
  • Park, Ho (Department of Clinical Laboratory Science, Wonkwang Health Science University)
  • 제갈승주 (원광보건대학교 임상병리과) ;
  • 민병운 (한려대학교 임상병리학과) ;
  • 박호 (원광보건대학교 임상병리과)
  • Received : 2015.10.30
  • Accepted : 2015.11.07
  • Published : 2015.12.30
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Abstract

Curcumin, a major polyphenolic compound of turmeric, is well known to prevent non-alcoholic steatohepatitis (NASH) related to obesity. The aim of the study was to investigate the effect of curcumin on hepatic fibrosis induced by carbon tetrachloride ($CCl_4$) in obese mice. $CCl_4$ was administrated in mice fed a normal diet (ND) or a high fat diet (HFD) for 7 weeks together with or without curcumin. It was conducted to examine for metabolic profiles, adipocyte size, and liver fibrosis by serum biochemistry, histology and immunohistochemistry. Also, Apoptosis of hepatic cells was determined by the TUNEL method. Treatment with curcumin significantly lowered the body weight, fasting glucose, serum AST and ALT, and decreased the adipocyte size, the number of macrophage and mast cells in adipose tissue, and collagen deposition in liver tissue in the HFD+$CCl_4$ group compared with the findings of the HFD+$CCl_4$ group. In contrast, treatment with curcumin on the ND+$CCl_4$ group did not show a significant difference except the body weight and mast cell number when compared with the ND+$CCl_4$ group. Furthermore, curcumin significantly reduced the number of parenchymal apoptotic cells, whereas it increased the number of non-parenchymal apoptotic cells, especially resembling an activated hepatic stellate cell in the liver. Taken together, this data suggests that curcumin might be an effective antifibrotic drug for the prevention of liver disease progression in obese mice. Thus, the development of curcumin as a therapy for obesity and liver fibrosis is supported.

커큐민(curcumin)은 강황 내 주요 폴리페놀 화합물의 한 성분으로 비만과 관련된 비알코올성 지방간염을 막아 주는 것으로 잘 알려져 있다. 이 연구의 목적은 고지방 식이로 키운 비만 마우스에서 사염화탄소($CCl_4$)로 유발한 간섬유증에 미치는 커큐민의 보호효과를 조사하기 위해 시도하였다. 군간 비교를 위해, 정상 식이와 고지방 식이로 키운 마우스에 7주간 $CCl_4$를 투여하면서 동시에 커큐민을 투여한 것과 투여하지 않은 군으로 나누었으며, 체중이나 혈당과 같은 대사 프로파일이나 지방세포의 크기 및 간섬유증의 변화를 조사하기 위해 혈청 생화학적 검사, 조직학적 검사 및 면역조직화학적 검사를 수행하였다. 또한 간세포 내자멸세포의 관찰을 위해 TUNEL 법을 사용하였다. 그 결과 고지방식이+$CCl_4$ 마우스에 커큐민을 투여한 군에서는 투여하지 않은 군에 비해 체중, 공복혈당 수치, 혈청 AST, ALT 수치가 낮았고, 지방조직 내의 지방세포 크기와 대식세포 및 비만세포 수가 감소하였다. 이와 반대로 정상식이+$CCl_4$ 마우스에 커큐민을 투여한 경우에는 투여하지 않은 군에 비해 체중과 비만세포 수 이외에는 통계학적인 차이가 없었다. 더욱이 커큐민은 간조직의 간실질세포의 자멸세포 수는 줄인 반면 활성 간성상세포 모양의 비실질세포의 자멸세포 수를 증가시켰다. 이 결과를 종합해 볼 때 커큐민은 비만 마우스의 간질환 진행에서 효과적인 항섬유 치료제로서 사용할 수 있을 것으로 사료된다.

Keywords

References

  1. Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. 2009, 41:40-59. https://doi.org/10.1016/j.biocel.2008.06.010
  2. Aggarwal BB, Sung B. Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends Pharmacol Sci. 2009, 30:85-94. https://doi.org/10.1016/j.tips.2008.11.002
  3. Altintas MM, Azad A, Nayer B, Contreras G, Zaias J, Faul C, et al. Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice. J Lipid Res. 2011, 52:480-488. https://doi.org/10.1194/jlr.M011338
  4. Bruck R, Ashkenazi M, Weiss S, Goldiner I, Shapiro H, Aeed H, et al. Prevention of liver cirrhosis in rats by curcumin. Liver Int. 2007, 27:373-383. https://doi.org/10.1111/j.1478-3231.2007.01453.x
  5. Charlton M, Krishnan A, Viker K, Sanderson S, Cazanave S, McConico A, et al. Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis, and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol. 2011, 301:825-834. https://doi.org/10.1152/ajpgi.00145.2011
  6. Chheda TK, Shivakumar P, Sadasivan SK, Chanderasekharan H, Moolemath Y, Oommen AM, et al. Fast food diet with CCl4 micro-dose induced hepatic fibrosis -a novel animal model. BMC Gastroenterol. 2014, 14:89-97. https://doi.org/10.1186/1471-230X-14-89
  7. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006, 43:99-112. https://doi.org/10.1002/hep.20973
  8. Fu Y, Zheng S, Lin J, Ryerse J, Chen A. Curcumin protects the rat liver from CCl4-caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation. Mol Pharmacol. 2008, 73:399-409. https://doi.org/10.1124/mol.107.039818
  9. Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol. 2011, 6:425-456. https://doi.org/10.1146/annurev-pathol-011110-130246
  10. Ito M, Suzuki J, Tsujioka S, Sasaki M, Gomori A, Shirakura T, et al. Longitudinal analysis of murine steatohepatitis model induced by chronic exposure to high-fat diet. Hepatol Res. 2007, 37:50-57. https://doi.org/10.1111/j.1872-034X.2007.00008.x
  11. Kang HC, Nan JX, Park PH, Kim JY, Lee SH, Woo SW, et al. Curcumin inhibits collagen synthesis and hepatic stellate cell activation in-vivo and in-vitro. J Pharm Pharmacol. 2002, 54:119-126. https://doi.org/10.1211/0022357021771823
  12. Kamalakkannan N, Rukkumani R, Varma PS, Viswanathan P, Rajasekharan KN, Menon VP. Comparative effects of curcumin and an analogue of curcumin in carbon tetrachloride-induced hepatotoxicity in rats. Basic Clin Pharmacol Toxicol. 2005, 97:15-21. https://doi.org/10.1111/j.1742-7843.2005.pto_97103.x
  13. Lim Y. The protective effects of green tea catechin on the bleomycin and cyclophosphamide induced cytotoxicity. Korean J Clin Lab Sci. 2014, 46:75-78. https://doi.org/10.15324/kjcls.2014.46.2.75
  14. Lubbad A, Oriowo MA, Khan I. Curcumin attenuates inflammation through inhibition of TLR-4 receptor in experimental colitis. Mol Cell Biochem. 2009, 322:127-135. https://doi.org/10.1007/s11010-008-9949-4
  15. Nakamura A1, Terauchi Y. Lessons from mouse models of high-fat diet-induced NAFLD. Int J Mol Sci. 2013, 14:21240-21257. https://doi.org/10.3390/ijms141121240
  16. Park EJ, Jeon CH, Ko G, Kim J, Sohn DH. Protective effect of curcumin in rat liver injury induced by carbon tetrachloride. J Pharm Pharmacol. 2000, 52:437-440. https://doi.org/10.1211/0022357001774048
  17. Priya S, Sudhakaran PR. Cell survival, activation and apoptosis of hepatic stellate cells: modulation by extracellular matrix proteins. Hepatol Res. 2008, 38:1221-1232.
  18. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006, 116:1793-1801. https://doi.org/10.1172/JCI29069
  19. Shao W, Yu Z, Chiang Y, Yang Y, Chai T, Foltz W, et al. Curcumin prevents high fat diet induced insulin resistance and obesity via attenuating lipogenesis in liver and inflammatory pathway in adipocytes. PLoS One. 2012, 7(1):e28784. https://doi.org/10.1371/journal.pone.0028784
  20. Sharma RA, Ireson CR, Verschoyle RD, Hill KA, Williams ML, Leuratti C. et al. Effects of dietary curcumin on glutathione S-transferase and malondialdehyde-DNA adducts in rat liver and colon mucosa: relationship with drug levels. Clin Cancer Res. 2001, 7:1452-1458.
  21. Shim MJ, Kang YJ. Relationships between metabolic syndrome component and depression, stress. Korean J Clin Sci. 2014, 46:68-74. https://doi.org/10.15324/kjcls.2014.46.2.68
  22. Wang Y, Cheng M, Zhang B, Nie F, Jiang H. Dietary supplementation of blueberry juice enhances hepatic expression of metallothionein and attenuates liver fibrosis in rats. PLoS One. 2013, 8(3):e58659. https://doi.org/10.1371/journal.pone.0058659
  23. Weber LW, Boll M, Stampfl A. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol. 2003, 33:105-136. https://doi.org/10.1080/713611034
  24. Weisberg SP, Leibel R, Tortoriello DV. Dietary curcumin significantly improves obesity-associated inflammation and diabetes in mouse models of diabesity. Endocrinology. 2008, 149:3549-3558. https://doi.org/10.1210/en.2008-0262
  25. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001, 7:941-946. https://doi.org/10.1038/90984

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