The effect of fucoxanthin on the development of CCl₄-induced liver fibrosis

Background. According to current concepts regarding hepatic fibrosis, myofibroblast differentiation from stellate cells, regulated by transforming growth factor-β (TGF-β), is a key step in its pathogenesis. Hence, inhibition of TGF-β-dependent activation of hepatic stellate cells has been suggested as a promising strategy for preventing the disease development.

Aim. To explore whether the administration of fucoxanthin at a dose of 30 mg/kg is efficient in suppressing hepatic fibrosis.

Materials and Methods. The experiments were carried out on 30 outbred ICR/CD1 mice which have been divided into three groups: intact animals, animals with untreated hepatic fibrosis which has been induced by intraperitoneal injections of CCl₄ (2 μl/g, 6 weeks, twice per week), and animals which received fucoxanthin per os (30 mg/kg daily for 5 weeks) after inducing hepatic fibrosis as described above. Histological examination was performed by Sirius Red staining using the METAVIR fibrosis and activity score. Immunohistochemical analysis was performed by quantitation of α-SMA-positive myofibroblasts, CD45-positive leukocytes, and TIMP-1-positive regions. Further, we quantified TGF-β in liver homogenate as well as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the serum by means of enzyme-linked immunosorbent assay. An assessment of liver function was conducted by measuring serum alanine aminotransferase, aspartate aminotransferase, and albumin levels.

Results. Fucoxanthin decreased the number of myofibroblasts and leukocytes, the volume of connective tissue and TIMP-1-positive regions, and the level of TGF-β in the liver homogenate, altogether indicative of ameliorated hepatic fibrosis. In accord, treatment with fucoxanthin reduced serum IL-1β, TNF-α, alanine aminotransferase and aspartate aminotransferase, and increased serum albumin.

Conclusion. Treatment with fucoxanthin at a dose of 30 mg/kg has an antifibrotic effect and diminishes liver fibrosis.

1. Tan Z, Sun H, Xue T, Gan C, Liu H, Xie Y, Yao Y, Ye T. Liver Fibrosis: Therapeutic Targets and Advances in Drug Therapy. Front Cell Dev Biol. 2021;9:730176. https://doi.org/10.3389/fcell.2021.730176

2. Cai X, Wang J, Wang J, Zhou Q, Yang B, He Q, Weng Q. Intercellular crosstalk of hepatic stellate cells in liver fibrosis: New insights into therapy. Pharmacol Res. 2020;155:104720. https://doi.org/10.1016/j.phrs.2020.104720

3. Pakshir P, Hinz B. The big five in fibrosis: Macrophages, myofibroblasts, matrix, mechanics, and miscommunication. Matrix Biol. 2018;68-69:81-93. https://doi.org/10.1016/j.matbio.2018.01.019

4. Lemoinne S, Cadoret A, El Mourabit H, Thabut D, Housset C. Origins and functions of liver myofibroblasts. Biochim. Biophys. Acta. 2013;1832(7):948-954. https://doi.org/10.1016/j.bbadis.2013.02.019

5. Puche JE, Saiman Y, Friedman SL. Hepatic stellate cells and liver fibrosis. Compr Physiol. 2013;3(4):1473-1492. https://doi.org/10.1002/cphy.c120035

6. Barnes JL, Gorin Y. Myofibroblast differentiation during fibrosis: role of NAD(P)H oxidases. Kidney Int. 2011;79(9):944-956. https://doi.org/10.1038/ki.2010.516

7. Pohlers D, Brenmoehl J, Löffler I, Müller CK, Leipner C, Schultze-Mosgau S, Stallmach A, Kinne RW, Wolf G. TGF-beta and fibrosis in different organs - molecular pathway imprints. Biochim Biophys Acta. 2009;1792(8):746-756. https://doi.org/10.1016/j.bbadis.2009.06.004

8. Hu HH, Chen DQ, Wang YN, Feng YL, Cao G, Vaziri ND, Zhao YY. New insights into TGF-β/Smad signaling in tissue fibrosis. Chem Biol Interact. 2018;292:76-83. https://doi.org/10.1016/j.cbi.2018.07.008

9. Xu F, Liu C, Zhou D, Zhang L. TGF-β/SMAD Pathway and Its Regulation in Hepatic Fibrosis. J Histochem Cytochem. 2016;64(3):157-167. https://doi.org/10.1369/0022155415627681

10. Ong CH, Tham CL, Harith HH, Firdaus N, Israf DA. TGF-β-induced fibrosis: A review on the underlying mechanism and potential therapeutic strategies. Eur J Pharmacol. 2021;911:17451 https://doi.org/10.1016/j.ejphar.2021.174510

11. Kim MB, Bae M, Hu S, Kang H, Park YK, Lee JY. Fucoxanthin exerts anti-fibrogenic effects in hepatic stellate cells. Biochem Biophys Res Commun. 2019;513(3):657-662. https://doi.org/10.1016/j.bbrc.2019.04.052

12. Bonet ML, Canas JA, Ribot J, Palou A. Carotenoids and their conversion products in the control of adipocyte function, adiposity and obesity. Arch Biochem Biophys. 2015;572:112-125. https://doi.org/10.1016/j.abb.2015.02.022

13. Liu M, Li W, Chen Y, Wan X, Wang J. Fucoxanthin: A promising compound for human inflammation-related diseases. Life Sci. 2020;255:117850. https://doi.org/10.1016/j.lfs.2020.117850

14. Grebnev DYu, Maklakova IYu, Titova DI, Permyakov NS. Geroprotective properties of fucoxanthin. Ural Medical Journal. 2022;21(5):94-101. (In Russ). https://doi.org/10.52420/2071-5943-2022-21-5-94-101

15. Grebnev DJu, Slautin VN, Maklakova IJu, Beresneva OY, Konyshev KY. Mechanisms of antifibrotic action of placental multipotent mesenchymal stromal cells. Vestn Ural Med Akad Nauki. = Journal of Ural Medical Academic Science. 2022;19(4):355-364. (In Russ). https://doi.org/10.22138/2500-0918-2022-19-4-355-364

16. Sangeetha RK, Bhaskar N, Divakar S, Baskaran V. Bioavailability and metabolism of fucoxanthin in rats: structural characterization of metabolites by LC-MS (APCI). Mol Cell Biochem. 2010;333(1-2):299-310. https://doi.org/10.1007/s11010-009-0231-1

17. Kim KN, Heo SJ, Yoon WJ, Kang SM, Ahn G, Yi TH, Jeon YJ. Fucoxanthin inhibits the inflammatory response by suppressing the activation of NF-κB and MAPKs in lipopolysaccharide-induced RAW 264.7 macrophages. Eur J Pharmacol. 2010;649(1-3):369-375. https:// doi.org/10.1016/j.ejphar.2010.09.032

18. Goodman ZD. Grading and staging systems for inflammation and fibrosis in chronic liver diseases. J Hepatol. 2007;47(4):598-607. https:// doi.org/10.1016/j.jhep.2007.07.006

19. Shiratori K, Ohgami K, Ilieva I, Jin XH, Koyama Y, Miyashita K, Yoshida K, Kase S, Ohno S. Effects of fucoxanthin on lipopolysaccharide-induced inflammation in vitro and in vivo. Exp Eye Res. 2005;81(4):422-428. https://doi.org/ 10.1016/j.exer.2005.03.002

20. Tan CP, Hou YH. First evidence for the anti-inflammatory activity of fucoxanthin in high-fat-diet-induced obesity in mice and the antioxidant functions in PC12 cells. Inflammation. 2014;37(2):443-450. https://doi.org/10.1007/s10753-013-9757-1

21. Meier RPH, Meyer J, Montanari E, Lacotte S, Balaphas A, Muller YD, Clément S, Negro F, Toso C, Morel P, Buhler LH. Interleukin-1 Receptor Antagonist Modulates Liver Inflammation and Fibrosis in Mice in a Model-Dependent Manner. Int J Mol Sci. 2019;20(6):1295. https://doi.org/10.3390/ijms20061295

22. Bae M, Kim MB, Park YK, Lee JY. Health benefits of fucoxanthin in the prevention of chronic diseases. Biochim Biophys Acta Mol Cell Biol Lipids. 2020;1865(11):158618. https://doi.org/10.1016/j.bbalip.2020.158618

23. Kisseleva T, Brenner DA. Inactivation of myofibroblasts during regression of liver fibrosis. Cell Cycle. 2013;12(3):381-382. https://doi.org/10.4161/cc.23549