Modulation of IKKβ/NF-κB and TGF-β1/Smad via Fuzheng Huayu recipe involves in prevention of nutritional steatohepatitis and fibrosis in mice

Document Type : Original Article

Authors

Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China

Abstract

Objective(s):Fuzheng Huayu recipe (FZHY) exerts significant protective effects against liver fibrosis by strengthening the body’s resistance and removing blood stasis. However, the molecular mechanisms through which FZHY affects liver fibrosis are still unclear. In this study, we examined the expression levels of factors involved in the inhibitor κB kinase-β (IKK-β)/nuclear factor-κB (NF-κB) and transforming growth factor beta 1 (TGF-β1)/Smad signaling pathways to elucidate whether FZHY could attenuate nutritional steatohepatitis and fibrosis in mice.
Materials and Methods: C57BL/6J mice were fed with methionine-choline deficient (MCD) diet for 8 weeks to induce fibrotic steatohepatitis. FZHY and/or heme oxygenase-1 (HO-1) chemical inducer (hemin) were administered to mice. The effects of FZHY alone and in combination with hemin were assessed by comparing the severity of hepatic injury, activation of hepatic stellate cells (HSCs), and the expression of oxidative stress, inflammation and fibrogenesis related genes.
Results: Administration of FZHY, hemin and FZHY plus hemin significantly ameliorated liver injury. Additionally, our analysis indicated that administration of these agents significantly attenuated oxidative stress, downregulated the expression of pro-inflammatory and pro-fibrotic genes, including IKK-β, NF-κB, monocyte chemoattractant protein-1 (MCP-1), α-smooth muscle actin            (α-SMA), TGF-β1, Smad3 and Smad4, and upregulated the expression of the antifibrogenic gene Smad7 (P< 0.001).
Conclusion: FZHY-containing therapies prevented nutritional steatohepatitis and fibrosis through modulating the expression of factors associated with the IKKβ/NF-κB and TGF-β1/Smad signaling pathways and oxidative stress related genes.

Keywords

References

1. Basaranoglu M, Basaranoglu G, Sabuncu T, Sentürk H. Fructose as a key player in the development of fatty liver disease. World J Gastroenterol 2013; 19:1166-1172.
2. Afzali A, Berry K, Ioannou GN. Excellent posttransplant survival for patients with nonalcoholic steatohepatitis in the United States. Liver Transpl 2012; 18:29-37.
3. Friedman SL. Liver fibrosis in 2012: Convergent pathways that cause hepatic fibrosis in NASH. Nat Rev Gastroenterol Hepatol 2013; 10:71-72.
4. Day CP, James OF. Hepatic steatosis: innocent bystander or quity party? Hepatology 1998; 27:1463-1466.
5. Xie H, Tao Y, Lv J, Liu P, Liu C. Proteomic analysis of the effect of fuzheng huayu recipe on fibrotic liver in rats. Evid Based Complement Alternat Med 2013; 2013:972863.
6. Liu C, Hu Y, Xu L, Liu C, Liu P. Effect of Fuzheng Huayu formula and its actions against liver fibrosis. Chin Med 2009; 4:12.
7. Jia YH, Wang RQ, Mi HM, Kong LB, Ren WG, et al. Fuzheng Huayu recipe prevents nutritional fibrosing steatohepatitis in mice. Lipids Health Dis 2012; 11:45-55.
8. García-Galiano D, Sánchez-Garrido MA, Espejo I, Montero JL, Costán G, Marchal T, et al. IL-6 and IGF-1 are independent prognostic factors of liver steatosis and non-alcoholic steatohepatitis in morbidly obese patients. Obes Surg 2007; 17:493-503.
9. Yilmaz O, Ersan Y, Dilek Ozsahin A, Ihsan Ozturk A, Ozkan Y. Consequences of the combined α-tocopherol, ascorbic acid and α-lipoic acid on the glutathione, cholesterol and fatty acid composition in muscle and liver of diabetic rats. Iran J Basic Med Sci 2013; 16:165-172.
10. Wang RQ, Nan YM, Wu WJ, Kong LB, Han F, Zhao SX, et al. Induction of heme oxygenase-1 protects against nutritional fibrosing steatohepatitis in mice. Lipids Health Dis 2011; 10:31-41.
11. Yu J, Chu ES, Wang R, Wang S, Wu CW, Wong VW, et al. Heme oxygenase-1 protects against steatohepatitis in both cultured hepatocytes and mice. Gastroenterol 2010; 138:694-704.
12. Yu J, Ip E, Dela Peña A, Hou JY, Sesha J, Pera N, et al. COX-2 induction in mice with experimental nutritional steatohepatitis: role as pro-inflammatory mediator. Hepatol 2006; 43:826-836.
13. Basaranoglu M, Basaranoglu G, Sentürk H. From fatty liver to fibrosis: a tale of "second hit". World J Gastroenterol 2013; 19:1158-1165.
14. Tsochatzis EA, Papatheodoridis GV, Archimandritis AJ. Adipokines in nonalcoholic steatohepatitis: from pathogenesis to implications in diagnosis and therapy. Mediators Inflamm 2009; 2009:831670.
15. Cohen-Naftaly M, Friedman SL. Current status of novel antifibrotic therapies in patients with chronic liver disease. Therap Adv Gastroenterol 2011; 4:391-417. 
16. Wang QM, Du JL, Duan ZJ, Guo SB, Sun XY, Liu Z. Inhibiting heme oxygenase-1 attenuates rat liver fibrosis by removing iron accumulation. World J Gastroenterol 2013; 19:2921-2934.
17. Grochot-Przeczek A, Dulak J, Jozkowicz A. Haem oxygenase-1: non-canonical roles in physiology and pathology. Clin Sci (Lond) 2012; 122:93-103.
18. Wasmuth HE, Tacke F, Trautwein C. Chemokines in liver inflammation and fibrosis. Semin Liver Dis 2010; 30:215-225.
19. Basaranoglu M, Basaranoglu G, Sabuncu T, Sentürk H. Fructose as a key player in the development of fatty liver disease. World J Gastroenterol 2013; 19:1166-1172.
20. Park HJ, Lee JY, Chung MY, Park YK, Bower AM, Koo SI, et al. Green tea extract suppresses NFκB activation and inflammatory responses in diet-induced obese rats with nonalcoholic steatohepatitis. J Nutr 2012; 142:57-63.
21. Liu C, Tao Q, Sun M, Wu JZ, Yang W, Jian P, et al. Kupffer cells are associated with apoptosis, inflammation and fibrotic effects in hepatic fibrosis in rats. Lab Invest 2010; 90:1805-1816.
22. Locatelli I, Sutti S, Vacchiano M, Bozzola C, Albano E. NF-κB1 deficiency stimulates the progression of non-alcoholic steatohepatitis (NASH) in mice by promoting NKT-cell-mediated responses. Clin Sci (Lond) 2013; 124:279-287.
23. Tuyama AC, Chang CY. Non-alcoholic fatty liver disease. J Diabetes 2012; 4:266-280.
24. Hansel B, Giral P, Nobecourt E, Chantepie S, Bruckert E, Chapman MJ, et al. Metabolic syndrome is associated with elevated oxidative stress and dysfunctional dense high-density lipoprotein particles displaying impaired antioxidative activity. J Clin Endocrinol Metab 2004; 89:4963-4971.
25. Saugspier M, Dorn C, Thasler WE, Gehrig M, Heilmann J, Hellerbrand C. Hop bitter acids exhibit anti-fibrogenic effects on hepatic stellate cells in vitro. Exp Mol Pathol 2012; 92:222-228.
26. Santos Rocha SW, Silva BS, Gomes FO, Soares e Silva AK, Raposo C, Barbosa KP, et al. Effect of diethylcarbamazine on chronic hepatic inflammation induced by alcohol in C57BL/6 mice. Eur J Pharmacol 2012; 689:194-203.
27. Oakley F, Teoh V, Ching-A-Sue G, Bataller R, Colmenero J, Jonsson JR, et al. Angiotensin II activates I kappaB kinase phosphorylation of RelA at Ser 536 to promote myofibroblast survival and liver fibrosis. Gastroenterol 2009; 136:2334-2344.
28. Luedde T, Schwabe RF. NF-κB in the liver--linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2011; 8:108-118.
29. Ghiassi-Nejad Z, Friedman SL. Advances in antifibrotic therapy. Expert Rev Gastroenterol Hepatol 2008; 2:803-816.
30. Li S, Wang L, Yan X, Wang Q, Tao Y, Li J, et al. Salvianolic acid B attenuates rat hepatic fibrosis via downregulating angiotensin II signaling. Evid Based Complement Alternat Med 2012; 2012:160726.
31. Yoshida K, Matsuzaki K. Differential Regulation of TGF-β/Smad Signaling in Hepatic Stellate Cells between Acute and Chronic Liver Injuries. Front Physiol 2012; 3:53.
32. Chai NL, Fu Q, Shi H, Cai CH, Wan J, Xu SP, et al. Oxymatrine liposome attenuates hepatic fibrosis via targeting hepatic stellate cells. World J Gastroenterol 2012; 18:4199-4206.
33. Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 2007; 13:1324-1332.
34. Dong C, Li HJ, Chang S, Liao HJ, Zhang ZP, Huang P, et al. A disintegrin and metalloprotease with thrombo-
spondin motif 2 may contribute to cirrhosis in humans through the transforming growth factor-β/SMAD pathway. Gut Liver 2013; 7:213-220.
35. Yang J, Zheng J, Wu L, Shi M, Zhang H, Wang X, et al. NDRG2 ameliorates hepatic fibrosis by inhibiting the TGF-β1/Smad pathway and altering the MMP2/TIMP2 ratio in rats. PLoS One 2011; 6:e27710.
36. Zong L, Qu Y, Xu MY, Dong YW, Lu LG. 18α-glycyrrhetinic acid down-regulates expression of type I and III collagen via TGF-Β1/Smad signaling pathway in human and rat hepatic stellate cells. Int J Med Sci 2012; 9:370-379.
37. Yoshida K, Matsuzaki K. Differential regulation of TGF-β/Smad signaling in hepatic stellate cells between acute and chronic liver injuries. Front Physiol 2012; 3:53. [M1] 
38. Szuster-Ciesielska A, Mizerska-Dudka M, Daniluk J, Kandefer-Szerszeń M. Butein inhibits ethanol-induced activation of liver stellate cells through TGF-β, NFκB, p38, and JNK signaling pathways and inhibition of oxidative stress. J Gastroenterol 2013; 48:222-237.
39. Wang QL, Yuan JL, Tao YY, Zhang Y, Liu P, Liu CH. Fuzheng Huayu recipe and vitamin E reverse renal interstitial fibrosis through counteracting TGF-beta1-induced epithelial-to-mesenchymal transition. J Ethnopharmacol 2010; 127:631-640.
.

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