Biomedical Science Letters (대한의생명과학회지)

The Korean Society for Biomedical Laboratory Sciences (대한의생명과학회)
권호 표지
DOI QR코드

DOI QR Code

The Herbal Composition Gangjihwan from Ephedra intermedia, Lithospermum erythrorhizon and Rheum palmatum Ameliorates Hepatic Inflammation and Fibrosis in Obese C57BL/6J Mice and HepG2 Cells

  • Yoon, Michung (Department of Biomedical Engineering, Mokwon University)
  • Received : 2017.02.17
  • Accepted : 2017.04.05
  • Published : 2017.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

It was demonstrated that Gangjihwan (DF), which is the herbal composition composed of Ephedra intermedia, Lithospermum erythrorhizon, and Rheum palmatum, inhibits obesity and hepatic steatosis in high fat diet (HFD)-fed obese mice. The aim of this study was to determine the effects of DF on visceral obesity, hepatic inflammation and fibrosis and the mechanism of actions involved in this process using in vivo and in vitro approaches. DF was extracted with water (DF-FW), 30% grain alcohol (DF-GA30), and 70% grain alcohol (DF-GA70). Administration of DF to HFD-fed control mice decreased visceral tissue mass and visceral adipocyte size without adverse effects. Visceral fat mass was decreased by DF-GA30 and DF-GA70, and visceral adipocyte size by all three DF extracts compared with obese control mice. Histological analysis revealed that three kinds of DF extracts reduced toluidine blue-stained mast cells and collagen accumulation in the liver, the extents of which were most eminent in DF-GA70-treated mice. DF-GA70 decreased the mRNA levels of the inflammation ($TNF{\alpha}$ and VCAM-1), fibrosis (${\alpha}-SMA$), and apoptosis (caspase 3) genes, but increasing the anti-apoptosis gene (Bcl-2) mRNA levels in the liver of obese control mice. Consistent with the in vivo data, GA-70 also altered the expression of inflammation genes ($TNF{\alpha}$ and MCP-1) in HepG2 cells. These results indicate that DF not only inhibits visceral obesity, but also ameliorates visceral obesity-induced hepatic inflammation and fibrosis and that this process may be mediated by regulating the hepatic expression of inflammatory and fibrogenic genes.

Keywords

References

  1. Angulo P. Nonalcoholic fatty liver disease. The New England Journal of Medicine. 2002. 346: 1221-1231. https://doi.org/10.1056/NEJMra011775
  2. Bataller R, Brenner DA. Liver fibrosis. Journal of Clinical Investigation. 2005. 115: 209-218. https://doi.org/10.1172/JCI24282
  3. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nature Medicine. 2005. 11: 183-190. https://doi.org/10.1038/nm1166
  4. Canbay A, Feldstein A, Baskin-Bey E, Bronk SF, Gores GJ. The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse. Journal of Pharmacology and Experimental Therapeutics. 2004. 308: 1191-1196.
  5. Cancello R, Tordjman J, Poitou C, Guilhem G, Bouillot JL, Hugol D, Coussieu C, Basdevant A, Bar Hen A, Bedossa P, Guerre-Millo M, Clement K. Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes. 2006. 55: 1554-1461. https://doi.org/10.2337/db06-0133
  6. Cao L, Quan XB, Zeng WJ, Yang XO, Wang MJ. Mechanism of hepatocyte apoptosis. Journal of Cell Death. 2016. 9: 19-29.
  7. Chan W, Tan A, Vethakkan S, Tah P, Vijayananthan A, Goh K. Non-alcoholic fatty liver disease in diabetics-prevalence and predictive factors in a multiracial hospital clinic population in Malaysia. Journal of Gastroenterology and Hepatology. 2013. 28: 1375-1383. https://doi.org/10.1111/jgh.12204
  8. Charlton M. Nonalcoholic fatty liver disease: a review of current understanding and future impact. Clinical Gastroenterology and Hepatology. 2004. 2: 1048-1058. https://doi.org/10.1016/S1542-3565(04)00440-9
  9. Chatzigeorgiou A, Chung KJ, Garcia-Martin R, Alexaki VI, Klotzsche-von Ameln A, Phieler J, Sprott D, Kanczkowski W, Tzanavari T, Bdeir M, Bergmann S, Cartellieri M, Bachmann M, Nikolakopoulou P, Androutsellis-Theotokis A, Siegert G, Bornstein SR, Muders MH, Boon L, Karalis KP, Lutgens E, Chavakis T. Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation. Hepatology. 2014. 60: 1196-1210. https://doi.org/10.1002/hep.27233
  10. Curat CA, Miranville A, Sengenes C, Diehl M, Tonus C, Busse R, Bouloumie A. From blood monocytes to adipose tissueresident macrophages: induction of diapedesis by human mature adipocytes. Diabetes. 2004. 53: 1285-1292. https://doi.org/10.2337/diabetes.53.5.1285
  11. Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006. 444: 881-887. https://doi.org/10.1038/nature05488
  12. Diehl AM. Hepatic complications of obesity. Gastroenterology Clinics of North America. 2005. 34: 45-61. https://doi.org/10.1016/j.gtc.2004.12.012
  13. Fan J. Epidemiology of alcoholic and nonalcoholic fatty liver disease in China. Journal of Gastroenterology and Hepatology. 2013. 28: 11-17.
  14. Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, Gores GJ. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology. 2003. 125: 437-443. https://doi.org/10.1016/S0016-5085(03)00907-7
  15. Gomez-Lechon MJ, Donato MT, Martinez-Romero A, Jimenez N, Castell JV, O'Connor JE. A human hepatocellular in vitro model to investigate steatosis. Chemico-Biological Interactions. 2007. 165: 106-116. https://doi.org/10.1016/j.cbi.2006.11.004
  16. Jeong S, Chae K, Jung YS, Rho YH, Lee J, Ha J, Yoon KH, Kim GC, Oh KS, Shin SS, Yoon M. The Korean traditional medicine Gyeongshingangjeehwan inhibits obesity through the regulation of leptin and PPARalpha action in OLETF rats. Journal of Ethnopharmacology. 2008. 119: 245-251. https://doi.org/10.1016/j.jep.2008.06.037
  17. Jeong S, Yoon M. Fenofibrate inhibits adipocyte hypertrophy and insulin resistance by activating adipose $PPAR{\alpha}$ in high fat diet-induced obese mice. Experimental & Molecular Medicine. 2009. 41: 397-405. https://doi.org/10.3858/emm.2009.41.6.045
  18. Koh JC, Loo WM, Goh KL, Sugano K, Chan WK, Chiu WY, Choi MG, Gonlachanvit S, Lee WJ, Lee WJ, Lee YY, Lesmana LA, Li YM, Liu CJ, Matsuura B, Nakajima A, Ng EK, Sollano JD, Wong SK, Wong VW, Yang Y, Ho KY, Dan YY. Asian consensus on the relationship between obesity and gastrointestinal and liver diseases. Journal of Gastroenterology and Hepatology. 2016. 31: 1405-1413. https://doi.org/10.1111/jgh.13385
  19. Liang H, Zhang L, Wang H, Tang J, Yang J, Wu C, Chen S. Inhibitory effect of gardenoside on free fatty acid-induced steatosis in HepG2 hepatocytes. International Journal of Molecular Sciences. 2015. 16: 27749-27756. https://doi.org/10.3390/ijms161126058
  20. Machado M, Marques-Vidal P, Cortez-Pinto H. Hepatic histology in obese patients undergoing bariatric surgery. Journal of Hepatology. 2006. 45: 600-606. https://doi.org/10.1016/j.jhep.2006.06.013
  21. Milic S, Stimac D. Nonalcoholic fatty liver disease/steatohepatitis: epidemiology, pathogenesis, clinical presentation and treatment. Digestive Diseases. 2012. 30: 158-162. https://doi.org/10.1159/000336669
  22. Mulder P, Morrison MC, Wielinga PY, van Duyvenvoorde W, Kooistra T, Kleemann R. Surgical removal of inflamed epididymal white adipose tissue attenuates the development of non-alcoholic steatohepatitis in obesity. International Journal of Obesity. 2016. 40: 675-684. https://doi.org/10.1038/ijo.2015.226
  23. Park SH, Jeon WK, Kim SH, Kim HJ, Park DI, Cho YK, Sung IK, Sohn CI, Keum DK, Kim BI. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. Journal of Gastroenterology and Hepatology. 2006. 21: 138-143. https://doi.org/10.1111/j.1440-1746.2005.04086.x
  24. Petersen KF, Dufour S, Feng J, Befroy D, Dziura J, Dalla Man C, Cobelli C, Shulman GI. Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men. Proceedings of the National Academy of Sciences. 2006. 103: 18273 -18277. https://doi.org/10.1073/pnas.0608537103
  25. Roh JS, Lee H, Woo S, Yoon M, Kim J, Park SD, Shin SS, Yoon M. Herbal composition Gambigyeongsinhwan from Curcuma longa, Alnus japonica, and Massa Medicata Fermentata inhibits lipid accumulation in 3T3-L1 cells and regulates obesity in Otsuka Long-Evans Tokushima Fatty rats. Journal of Ethnopharmacology. 2015. 171: 287-294. https://doi.org/10.1016/j.jep.2015.05.056
  26. Saile B, Matthes N, El Armouche H, Neubauer K, Ramadori G. The bcl, NFkappaB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-beta or TNF-alpha on activated hepatic stellate cells. European Journal of Cell Biology. 2001. 80: 554-561. https://doi.org/10.1078/0171-9335-00182
  27. Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006. 118: 1388-1393. https://doi.org/10.1542/peds.2006-1212
  28. Shin SS, Jung YS, Yoon KH, Choi S, Hong Y, Park D, Lee H, Seo BI, Lee HY, Yoon M. The Korean traditional medicine gyeongshingangjeehwan inhibits adipocyte hypertrophy and visceral adipose tissue accumulation by activating PPARalpha actions in rat white adipose tissues. Journal of Ethnopharmacology. 2010. 127: 47-54. https://doi.org/10.1016/j.jep.2009.09.052
  29. Tilg H, Moschen AR. Insulin resistance, inflammation, and nonalcoholic fatty liver disease. Trends in Endocrinology and Metabolism. 2008. 19: 371-379. https://doi.org/10.1016/j.tem.2008.08.005
  30. Van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI, Kench JG, London R, Peduto T, Chisholm DJ, George J. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology. 2008. 48: 449-457. https://doi.org/10.1002/hep.22350
  31. Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: Selected practical issues in their evaluation and management. Hepatology. 2009. 49: 306-317. https://doi.org/10.1002/hep.22603
  32. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. Journal of Clinical Investigation. 2003. 112: 1821-1830. https://doi.org/10.1172/JCI200319451
  33. Yoon S, Kim J, Lee H, Lee H, Lim J, Yang H, Shin SS, Yoon M. The effects of herbal composition Gambigyeongsinhwan on hepatic steatosis and inflammation in Otsuka Long-Evans Tokushima fatty rats and HepG2 cells. Journal of Ethnopharmacology. 2017. 195: 204-213. https://doi.org/10.1016/j.jep.2016.11.020
  34. Yu SJ, Kim W, Kim D, Yoon JH, Lee K, Kim JH, Cho EJ, Lee JH, Kim HY, Kim YJ, Kim CY. Visceral obesity predicts significant fibrosis in patients with nonalcoholic fatty liver disease. Medicine. 2015. 94: e2159. https://doi.org/10.1097/MD.0000000000002159