Journal of Nutrition and Health

  • 제56권6호
  • /
  • Pages.589-601
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  • 2023
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  • 2288-3886(pISSN)
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  • 2288-3959(eISSN)
한국영양학회 (The Korean Nutrition Society)
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Protective effects of baicalein treatment against the development of nonalcoholic steatohepatitis in mice induced by a methionine choline-deficient diet

  • Jiwon Choi (Department of Food and Nutrition, College of Human Ecology, Kyung Hee University) ;
  • Jayong Chung (Department of Food and Nutrition, College of Human Ecology, Kyung Hee University)
  • 투고 : 2023.10.23
  • 심사 : 2023.11.13
  • 발행 : 2023.12.31
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초록

Purpose: Baicalein, a natural flavone found in herbs, exhibits diverse biological activities. Nonalcoholic steatohepatitis (NASH) is an irreversible condition often associated with a poor prognosis. This study aimed to evaluate the effects of baicalein on the development of NASH in mice. Methods: Male C57BL/6J mice were randomly divided into four groups. Three groups were fed a methionine-choline-deficient (MCD) diet to induce NASH and were simultaneously treated with baicalein (at doses of 50 and 100 mg/kg) or vehicle only (sodium carboxymethylcellulose) through oral gavage for 4 weeks. The control group was fed a methionine-choline-sufficient (MCS) diet without the administration of baicalein. Results: The baicalein treatment significantly reduced serum levels of alanine aminotransferase and aspartate aminotransferase, suggestive of reduced liver damage. Histological analysis revealed a marked decrease in nonalcoholic fatty liver activity scores induced by the MCD diet in the mice. Similarly, baicalein treatment at both doses significantly attenuated the degree of hepatic fibrosis, as examined by Sirius red staining, and hepatocellular death, as examined by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Baicalein treatment attenuated MCD-diet-induced lipid peroxidation, as evidenced by lower levels of hepatic malondialdehyde and 4-hydroxynonenal, demonstrating a reduction in oxidative stress resulting from lipid peroxidation. Moreover, baicalein treatment suppressed hepatic protein levels of 12-lipoxygenase (12-Lox) induced by the MCD diet. In contrast, baicalein enhanced the activities of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. Additionally, baicalein treatment significantly reduced hepatic non-heme iron concentrations and hepatic ferritin protein levels in mice fed an MCD diet. Conclusion: To summarize, baicalein treatment suppresses hepatic lipid peroxidation, 12-Lox expression, and iron accumulation, all of which are associated with the attenuation of NASH progression.

키워드

과제정보

This study was supported by the National Research Foundation of Korea (NRF) funded by the Korean Government (MIST) (NRF2020R1F1A1075611).

참고문헌

  1. Le MH, Yeo YH, Li X, Li J, Zou B, Wu Y, et al. 2019 Global NAFLD prevalence: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2022; 20(12): 2809-2817.e28. https://doi.org/10.1016/j.cgh.2021.12.002
  2. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med 2018; 24(7): 908-922. https://doi.org/10.1038/s41591-018-0104-9
  3. Li P, Hu J, Shi B, Tie J. Baicalein enhanced cisplatin sensitivity of gastric cancer cells by inducing cell apoptosis and autophagy via Akt/mTOR and Nrf2/Keap 1 pathway. Biochem Biophys Res Commun 2020; 531(3): 320-327. https://doi.org/10.1016/j.bbrc.2020.07.045
  4. Hwang JM, Tseng TH, Tsai YY, Lee HJ, Chou FP, Wang CJ, et al. Protective effects of baicalein on tert-butyl hydroperoxide-induced hepatic toxicity in rat hepatocytes. J Biomed Sci 2005; 12(2): 389-397. https://doi.org/10.1007/s11373-005-1572-8
  5. Xiao T, Cui Y, Ji H, Yan L, Pei D, Qu S. Baicalein attenuates acute liver injury by blocking NLRP3 inflammasome. Biochem Biophys Res Commun 2021; 534: 212-218. https://doi.org/10.1016/j.bbrc.2020.11.109
  6. Huang HL, Wang YJ, Zhang QY, Liu B, Wang FY, Li JJ, et al. Hepatoprotective effects of baicalein against CCl4-induced acute liver injury in mice. World J Gastroenterol 2012; 18(45): 6605-6613. https://doi.org/10.3748/wjg.v18.i45.6605
  7. Sun W, Liu P, Wang T, Wang X, Zheng W, Li J. Baicalein reduces hepatic fat accumulation by activating AMPK in oleic acid-induced HepG2 cells and high-fat diet-induced non-insulin-resistant mice. Food Funct 2020; 11(1): 711-721. https://doi.org/10.1039/C9FO02237F
  8. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41(6): 1313-1321. https://doi.org/10.1002/hep.20701
  9. Brain JD, Heilig E, Donaghey TC, Knutson MD, Wessling-Resnick M, Molina RM. Effects of iron status on transpulmonary transport and tissue distribution of Mn and Fe. Am J Respir Cell Mol Biol 2006; 34(3): 330-337. https://doi.org/10.1165/rcmb.2005-0101OC
  10. Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J Hepatol 2018; 68(2): 268-279. https://doi.org/10.1016/j.jhep.2017.09.003
  11. Utzschneider KM, Kahn SE. Review: the role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2006; 91(12): 4753-4761. https://doi.org/10.1210/jc.2006-0587
  12. Narasimhan S, Gokulakrishnan K, Sampathkumar R, Farooq S, Ravikumar R, Mohan V, et al. Oxidative stress is independently associated with non-alcoholic fatty liver disease (NAFLD) in subjects with and without type 2 diabetes. Clin Biochem 2010; 43(10-11): 815-821. https://doi.org/10.1016/j.clinbiochem.2010.04.003
  13. Malaguarnera M, Di Rosa M, Nicoletti F, Malaguarnera L. Molecular mechanisms involved in NAFLD progression. J Mol Med (Berl) 2009; 87(7): 679-695. https://doi.org/10.1007/s00109-009-0464-1
  14. Shojaie L, Iorga A, Dara L. Cell death in liver diseases: a review. Int J Mol Sci 2020; 21(24): 9682.
  15. Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, et al. Hepatocyte apoptosis and Fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 2003; 125(2): 437-443. https://doi.org/10.1016/S0016-5085(03)00907-7
  16. Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol 2008; 48(6): 993-999. https://doi.org/10.1016/j.jhep.2008.02.011
  17. Van De Wier B, Koek GH, Bast A, Haenen GR. The potential of flavonoids in the treatment of nonalcoholic fatty liver disease. Crit Rev Food Sci Nutr 2017; 57(4): 834-855. https://doi.org/10.1080/10408398.2014.952399
  18. Jarukamjorn K, Jearapong N, Pimson C, Chatuphonprasert W. A high-fat, high-fructose diet induces antioxidant imbalance and increases the risk and progression of nonalcoholic fatty liver disease in mice. Scientifica (Cairo) 2016; 2016: 5029414.
  19. Heim KE, Tagliaferro AR, Bobilya DJ. Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem 2002; 13(10): 572-584. https://doi.org/10.1016/S0955-2863(02)00208-5
  20. Zhang J, Zhang H, Deng X, Zhang N, Liu B, Xin S, et al. Baicalin attenuates non-alcoholic steatohepatitis by suppressing key regulators of lipid metabolism, inflammation and fibrosis in mice. Life Sci 2018; 192: 46-54. https://doi.org/10.1016/j.lfs.2017.11.027
  21. Zhu X, Xiong T, Liu P, Guo X, Xiao L, Zhou F, et al. Quercetin ameliorates HFD-induced NAFLD by promoting hepatic VLDL assembly and lipophagy via the IRE1a/XBP1s pathway. Food Chem Toxicol 2018; 114: 52-60. https://doi.org/10.1016/j.fct.2018.02.019
  22. Xiao J, Ho CT, Liong EC, Nanji AA, Leung TM, Lau TY, et al. Epigallocatechin gallate attenuates fibrosis, oxidative stress, and inflammation in non-alcoholic fatty liver disease rat model through TGF/SMAD, PI3 K/Akt/FoxO1, and NF-kappa B pathways. Eur J Nutr 2014; 53(1): 187-199. https://doi.org/10.1007/s00394-013-0516-8
  23. 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(11): 26087-26124. https://doi.org/10.3390/ijms161125942
  24. Rolo AP, Teodoro JS, Palmeira CM. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic Biol Med 2012; 52(1): 59-69. https://doi.org/10.1016/j.freeradbiomed.2011.10.003
  25. Kaur G, Jabbar Z, Athar M, Alam MS. Punica granatum (pomegranate) flower extract possesses potent antioxidant activity and abrogates Fe-NTA induced hepatotoxicity in mice. Food Chem Toxicol 2006; 44(7): 984-993. https://doi.org/10.1016/j.fct.2005.12.001
  26. Ma P, Zhang S, Su X, Qiu G, Wu Z. Protective effects of icariin on cisplatin-induced acute renal injury in mice. Am J Transl Res 2015; 7(10): 2105-2114.
  27. Li X, Khan I, Xia W, Huang G, Liu L, Law BY, et al. Icariin enhances youth-like features by attenuating the declined gut microbiota in the aged mice. Pharmacol Res 2021; 168: 105587.
  28. Palladini G, Di Pasqua LG, Cagna M, Croce AC, Perlini S, Mannucci B, et al. MCD diet rat model induces alterations in zinc and iron during NAFLD progression from steatosis to steatohepatitis. Int J Mol Sci 2022; 23(12): 6817.
  29. Handa P, Morgan-Stevenson V, Maliken BD, Nelson JE, Washington S, Westerman M, et al. Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice. Am J Physiol Gastrointest Liver Physiol 2016; 310(2): G117-G127. https://doi.org/10.1152/ajpgi.00246.2015
  30. Qi J, Kim JW, Zhou Z, Lim CW, Kim B. Ferroptosis affects the progression of nonalcoholic steatohepatitis via the modulation of lipid peroxidation-mediated cell death in mice. Am J Pathol 2020; 190(1): 68-81. https://doi.org/10.1016/j.ajpath.2019.09.011
  31. Li X, Wang TX, Huang X, Li Y, Sun T, Zang S, et al. Targeting ferroptosis alleviates methionine-choline deficient (MCD)-diet induced NASH by suppressing liver lipotoxicity. Liver Int 2020; 40(6): 1378-1394. https://doi.org/10.1111/liv.14428
  32. Perez CA, Wei Y, Guo M. Iron-binding and anti-Fenton properties of baicalein and baicalin. J Inorg Biochem 2009; 103(3): 326-332. https://doi.org/10.1016/j.jinorgbio.2008.11.003
  33. Li M, Meng Z, Yu S, Li J, Wang Y, Yang W, et al. Baicalein ameliorates cerebral ischemia-reperfusion injury by inhibiting ferroptosis via regulating GPX4/ACSL4/ACSL3 axis. Chem Biol Interact 2022; 366: 110137.
  34. Lu MJ, Chen YS, Huang HS, Ma MC. Hypoxic preconditioning protects rat hearts against ischemia-reperfusion injury via the arachidonate12-lipoxygenase/transient receptor potential vanilloid 1 pathway. Basic Res Cardiol 2014; 109(4): 414.
  35. Dai C, Li H, Wang Y, Tang S, Velkov T, Shen J. Inhibition of oxidative stress and ALOX12 and NF-κB pathways contribute to the protective effect of baicalein on carbon tetrachloride-induced acute liver injury. Antioxidants 2021; 10(6): 976.
  36. Zhang XJ, Ji YX, Cheng X, Cheng Y, Yang H, Wang J, et al. A small molecule targeting ALOX12-ACC1 ameliorates nonalcoholic steatohepatitis in mice and macaques. Sci Transl Med 2021; 13(624): eabg8116.