Protective effect of oil from Cornus wilsoniana fruits against carbon tetrachloride-induced hepatic fibrosis in mice

  • Qiang Liu
  • Qiang Liu Hunan Provincial Key Laboratory of Oils & Fats Molecular Structure and Function; Hunan Academy of Forestry
  • Xiaohua Lei Central South University
  • Zhenyu Cao Central South University
  • Ju Zhang Central South University
  • Tao Kuang Central South University
  • Guoxing Liu Central South University
  • Yu Fang Central South University
  • Ke Qian Central South University
  • Jie Fu Central South University
  • Huihui Du Central South University
  • Likun Yan Central South University
  • Zhihong Xiao Hunan Provincial Key Laboratory of Oils & Fats Molecular Structure and Function; Hunan Academy of Forestry
  • Changzhu Li Hunan Provincial Key Laboratory of Oils & Fats Molecular Structure and Function; Hunan Academy of Forestry
  • Xundi Xu Central South University
Keywords: Cornus wilsoniana oil; Hepatic fibrosis; Oxidative stress; inflammation; TGF-β1


Background: Cornus wilsoniana Wanger is a widely distributed woody oil plant in south China; oil extracted from its fruits has been the main source of edible oil for local residents for hundreds of years. Previous studies have demonstrated that Cornus wilsoniana oil (CWO) has hypolipidemic activity in rats. However, the hepatoprotective effects of CWO and their underlying mechanisms are not clear.

Objective: The purpose of this study was to explore the protective effects and mechanisms of the CWO against carbon tetrachloride (CCl4)-induced hepatic fibrosis in mice. Methods: Hepatic fibrosis mouse model was induced by intraperitoneal injection with 1 mL/kg CCl4 (mixed 1:4 in olive oil) twice a week for 6 weeks. In the meantime, the mice were orally administrated with CWO (0.5, 2 mL/kg) once daily for 6 weeks. Serological changes as well as oxidative stress, inflammatory, and histological alteration in the liver were determined.

Results: The results showed that CWO significantly attenuated CCl4-induced serological changes in mice, as assessed by serum markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), procollagen III, collagen type IV, hyaluronic acid, and laminin. At the same time, CWO significantly improved CCl4-induced liver histological changes, as detected by hematoxylin and eosin (H&E), Sirius red, and Masson’s trichrome staining. In addition, treatment with CWO reduced oxidative stress and inflammation in the liver. Furthermore, CWO also reduced the expression of extracellular matrix (ECM) in liver induced by CCl4, and TGF-β1/Smad3 signaling may be involved in the process.

Conclusions: CWO ameliorates CCl4-induced hepatic fibrosis by attenuating hepatic oxidative stress, reducing hepatic inflammation and inhibiting TGF-β1/Smad3 signaling pathway in liver. CWO may be a potentially beneficial edible oil for the adjuvant treatment of hepatic fibrosis.


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  1. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115: 209–18. doi: 10.1172/JCI24282

  2. Lim YS, Kim WR. The global impact of hepatic fibrosis and end-stage liver disease. Clin Liver Dis 2008; 12: 733–46. doi: 10.1016/j.cld.2008.07.007

  3. Lackner C, Tiniakos D. Fibrosis and alcohol-related liver disease. J Hepatol 2019; 70: 294–304. doi: 10.1016/j.jhep.2018.12.003

  4. Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A, Lackner C, et al. Alcoholic liver disease. Nat Rev Dis Primers 2018; 4: 16. doi: 10.1038/s41572-018-0014-7

  5. Trautwein C, Friedman SL, Schuppan D, Pinzani M. Hepatic fibrosis: concept to treatment. J Hepatol 2015; 62: S15–24. doi: 10.1016/j.jhep.2015.02.039

  6. Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 2017; 14: 397–411. doi: 10.1038/nrgastro.2017.38

  7. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008; 88: 125–72. doi: 10.1152/physrev.00013.2007

  8. Iwaisako K, Jiang C, Zhang M, Cong M, Moore-Morris TJ, Park TJ, et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc Natl Acad Sci U S A 2014; 111: E3297–305. doi: 10.1073/pnas.1400062111

  9. Narayanankutty A, Palliyil DM, Kuruvilla K, Raghavamenon AC. Virgin coconut oil reverses hepatic steatosis by restoring redox homeostasis and lipid metabolism in male Wistar rats. J Sci Food Agric 2018; 98: 1757–64. doi: 10.1002/jsfa.8650

  10. Ogaly HA, Eltablawy NA, Abd-Elsalam RM. Antifibrogenic influence of Mentha piperita L. essential oil against CCl4-induced liver fibrosis in rats. Oxid Med Cell Longev 2018; 2018: 1–15. doi: 10.1155/2018/4039753

  11. Tian Z, Jia H, Jin Y, Wang M, Kou J, Wang C, et al. Chrysanthemum extract attenuates hepatotoxicity via inhibiting oxidative stress in vivo and in vitro. Food Nutr Res 2019; 63. doi: 10.29219/fnr.v63.1667

  12. Fu J, Zhang XW, Liu K, Li QS, Zhang LR, Yang XH, et al. Hypolipidemic activity in Sprague-Dawley rats and constituents of a novel natural vegetable oil from Cornus wilsoniana fruits. J Food Sci 2012; 77: H160–9. doi: 10.1111/j.1750-3841.2012.02786.x

  13. Neuman MG, Cohen LB, Nanau RM. Hyaluronic acid as a non-invasive biomarker of liver fibrosis. Clin Biochem 2016; 49: 302–15. doi: 10.1016/j.clinbiochem.2015.07.019

  14. Gudowska M, Cylwik B, Chrostek L. The role of serum hyaluronic acid determination in the diagnosis of liver fibrosis. Acta Biochim Pol 2017; 64: 451–7. doi: 10.18388/abp.2016_1443

  15. Parsian H, Rahimipour A, Nouri M, Somi MH, Qujeq D, Fard MK, et al. Serum hyaluronic acid and laminin as biomarkers in liver fibrosis. J Gastrointestin Liver Dis 2010; 19: 169–74.

  16. Doi K, Kurabe S, Shimazu N, Inagaki M. Systemic histopathology of rats with CCl4-induced hepatic cirrhosis. Lab Anim 1991; 25: 21–5. doi: 10.1258/002367791780808121

  17. Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: a translational success story. Gut 2015; 64: 830–41. doi: 10.1136/gutjnl-2014-306842

  18. Lee CP, Shih PH, Hsu CL, Yen GC. Hepatoprotection of tea seed oil (Camellia oleifera Abel.) against CCl4-induced oxidative damage in rats. Food Chem Toxicol 2007; 45: 888–95. doi: 10.1016/j.fct.2006.11.007

  19. Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW, et al. The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci 2015; 16: 26087–124. doi: 10.3390/ijms161125942

  20. Noori M, Jafari B, Hekmatdoost A. Pomegranate juice prevents development of non-alcoholic fatty liver disease in rats by attenuating oxidative stress and inflammation. J Sci Food Agric 2017; 97: 2327–32. doi: 10.1002/jsfa.8042

  21. Durasevic S, Jasnic N, Prokic M, Grigorov I, Martinovic V, Dordevic J, et al. The protective role of virgin coconut oil on the alloxan-induced oxidative stress in the liver, kidneys and heart of diabetic rats. Food Funct 2019; 10: 2114–24. doi: 10.1039/c9fo00107g

  22. Carnevale R, Pastori D, Nocella C, Cammisotto V, Bartimoccia S, Novo M, et al. Gut-derived lipopolysaccharides increase post-prandial oxidative stress via Nox2 activation in patients with impaired fasting glucose tolerance: effect of extra-virgin olive oil. Eur J Nutr 2019; 58: 843–51. doi: 10.1007/s00394-018-1718-x

  23. Iredale JP. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest 2007; 117: 539–48. doi: 10.1172/JCI30542

  24. Seki E, Schwabe RF. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology 2015; 61: 1066–79. doi: 10.1002/hep.27332

  25. Choi I, Kang HS, Yang Y, Pyun KH. IL-6 induces hepatic inflammation and collagen synthesis in vivo. Clin Exp Immunol 1994; 95: 530–5. doi: 10.1111/j.1365-2249.1994.tb07031.x

  26. Yin M, Wheeler MD, Kono H, Bradford BU, Gallucci RM, Luster MI, et al. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology 1999; 117: 942–52. doi: 10.1016/s0016-5085(99)70354-9

  27. Osawa Y, Hoshi M, Yasuda I, Saibara T, Moriwaki H, Kozawa O. Tumor necrosis factor-alpha promotes cholestasis-induced liver fibrosis in the mouse through tissue inhibitor of metalloproteinase-1 production in hepatic stellate cells. Plos One 2013; 8: e65251. doi: 10.1371/journal.pone.0065251

  28. Connolly MK, Bedrosian AS, Mallen-St CJ, Mitchell AP, Ibrahim J, Stroud A, et al. In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-alpha. J Clin Invest 2009; 119: 3213–25. doi: 10.1172/JCI37581

  29. Valente AJ, Rozek MM, Sprague EA, Schwartz CJ. Mechanisms in intimal monocyte-macrophage recruitment. A special role for monocyte chemotactic protein-1. Circulation 1992; 86: I20–5.

  30. Lai SS, Fu X, Cheng Q, Yu ZH, Jiang EZ, Zhao DD, et al. HSC-specific knockdown of GGPPS alleviated CCl4-induced chronic liver fibrosis through mediating RhoA/Rock pathway. Am J Transl Res 2019; 11: 2382–92.

  31. Cao F, Zhang Y, Li W, Shimizu K, Xie H, Zhang C. Mogroside IVE attenuates experimental liver fibrosis in mice and inhibits HSC activation through downregulating TLR4-mediated pathways. Int Immunopharmacol 2018; 55: 183–92. doi: 10.1016/j.intimp.2017.12.023

  32. Han M, Liu X, Liu S, Su G, Fan X, Chen J, et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces hepatic stellate cell (HSC) activation and liver fibrosis in C57BL6 mouse via activating Akt and NF-kappaB signaling pathways. Toxicol Lett 2017; 273: 10–19. doi: 10.1016/j.toxlet.2017.03.013

  33. Lewindon PJ, Pereira TN, Hoskins AC, Bridle KR, Williamson RM, Shepherd RW, et al. The role of hepatic stellate cells and transforming growth factor-beta(1) in cystic fibrosis liver disease. Am J Pathol 2002; 160: 1705–15. doi: 10.1016/s0002-9440(10)61117-0

  34. Peng X, Dai C, Liu Q, Li J, Qiu J. Curcumin attenuates on carbon tetrachloride-induced acute liver injury in mice via modulation of the Nrf2/HO-1 and TGF-beta1/Smad3 pathway. Molecules 2018; 23. doi: 10.3390/molecules23010215

  35. Seki E, De Minicis S, Österreicher CH, Kluwe J, Osawa Y, Brenner DA, et al. TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat Med 2007; 13: 1324–32. doi: 10.1038/nm1663

How to Cite
Liu Q, Liu Q, Lei X, Cao Z, Zhang J, Kuang T, Liu G, Fang Y, Qian K, Fu J, Du H, Yan L, Xiao Z, Li C, Xu X. Protective effect of oil from Cornus wilsoniana fruits against carbon tetrachloride-induced hepatic fibrosis in mice. fnr [Internet]. 2020May8 [cited 2020Jun.3];64. Available from:
Original Articles