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Vitamin E Ameliorates Lipid Metabolism in Mice with Nonalcoholic Fatty Liver Disease via Nrf2/CES1 Signaling Pathway

  • Wenxi He
  • Yanjiao Xu
  • Xiuhua Ren
  • Dong Xiang
  • Kai Lei
  • Chengliang Zhang
  • Dong LiuEmail author
Original Article
  • 54 Downloads

Abstract

Background

Vitamin E has been reported to have a beneficial effect on nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanism of action has not yet been clearly defined.

Aim

We aimed to evaluate the effects and mechanisms of vitamin E on lipid and glucose homeostasis both in vivo and in vitro.

Methods

An NAFLD model was established in C57BL/6 mice fed a 30% fructose solution for 8 weeks. Subsequently, NAFLD mice were given vitamin E (70 mg/kg) for 2 weeks. In addition, L02 cells were treated with 5 mM fructose and 100 nM vitamin E to explore the potential mechanisms of action.

Results

Vitamin E reversed the impaired glucose tolerance of fructose-treated mice. Histopathological examination showed that liver steatosis was significantly relieved in vitamin E-treated mice. These effects may be attributed to the upregulation of nuclear factor erythroid-2-related factor 2 (Nrf2), carboxylesterase 1 (CES1), and downregulated proteins involved in lipid synthesis by vitamin E treatment. In vivo, vitamin E also significantly reduced lipid accumulation in fructose-treated L02 cells, and the Nrf2 inhibitor ML385 reversed the protective effects of vitamin E.

Conclusion

These data indicated that the therapeutic effects of vitamin E on lipid and glucose homeostasis may be associated with activation of the Nrf2/CES1 signaling pathway.

Keywords

Carboxylesterase 1 Fructose Glucose homeostasis Lipid Nonalcoholic fatty liver disease Vitamin E 

Notes

Acknowledgments

This study was supported by National Natural Science Foundation of China (NSFC) (No. 81670521), Hubei provincial health and Family Planning Commission (No. ZY2019Z003), Hubei Provincial Natural Science Foundation of China (No. 2018CFB583), and National Major Scientific and Technological Special Project for “Significant New Drugs Development” (No. 2017ZX09304022).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests or non-financial competing interests. All authors agree to publish.

Supplementary material

10620_2019_5657_MOESM1_ESM.docx (286 kb)
Supplementary material 1 (DOCX 282 kb)

References

  1. 1.
    Younossi ZM, Loomba R, Rinella ME, et al. Current and future therapeutic regimens for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Hepatology (Baltimore, Md). 2018;68:361–371.CrossRefGoogle Scholar
  2. 2.
    Musso G, Cassader M, Gambino R. Nonalcoholic steatohepatitis: emerging molecular targets and therapeutic strategies. Nat Rev Drug Discov. 2016;15:249–274.CrossRefGoogle Scholar
  3. 3.
    Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology (Baltimore, Md). 2018;67:328–357.CrossRefGoogle Scholar
  4. 4.
    Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305:1659–1668.CrossRefGoogle Scholar
  5. 5.
    Lavine JE. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr. 2000;136:734–738.CrossRefGoogle Scholar
  6. 6.
    Zingg JM. Vitamin E: a role in signal transduction. Annu Rev Nutr. 2015;35:135–173.CrossRefGoogle Scholar
  7. 7.
    Xu JS, Li YY, Chen WD, et al. Hepatic carboxylesterase 1 is essential for both normal and farnesoid x receptor-controlled lipid homeostasis. Hepatology (Baltimore, Md). 2014;59:1761–1771.CrossRefGoogle Scholar
  8. 8.
    Maruichi T, Fukami T, Nakajima M, Yokoi T. Transcriptional regulation of human carboxylesterase 1A1 by nuclear factor-erythroid 2 related factor 2 (Nrf2). Biochem Pharmacol. 2010;79:288–295.CrossRefGoogle Scholar
  9. 9.
    Yilmaz Y. Review article: fructose in nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2012;35:1135–1144.CrossRefGoogle Scholar
  10. 10.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–419.CrossRefGoogle Scholar
  11. 11.
    DeFilippis AP, Blaha MJ, Martin, et al. Nonalcoholic fatty liver disease and serum lipoproteins: the multi-ethnic study of atherosclerosis. Atherosclerosis. 2013;227:429–436.CrossRefGoogle Scholar
  12. 12.
    McCarty MF. High-dose biotin, an inducer of glucokinase expression, may synergize with chromium picolinate to enable a definitive nutritional therapy for type II diabetes. Med Hypotheses. 1999;52:401–406.CrossRefGoogle Scholar
  13. 13.
    Alwahsh SM, Gebhardt R. Dietary fructose as a risk factor for nonalcoholic fatty liver disease (NAFLD). Archiv Toxicol. 2017;91:1545–1563.CrossRefGoogle Scholar
  14. 14.
    Ouyang X, Cirillo P, Sautin Y, et al. Fructose consumption as a risk factor for nonalcoholic fatty liver disease. J Hepatol. 2008;48:993–999.CrossRefGoogle Scholar
  15. 15.
    Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol. 2010;7:251–264.CrossRefGoogle Scholar
  16. 16.
    Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142:1592–1609.CrossRefGoogle Scholar
  17. 17.
    Sato K, Gosho M, Yamamoto T, et al. Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Nutrition. 2015;31:923–930.CrossRefGoogle Scholar
  18. 18.
    Quiroga AD, Li LN, Trotzmuller M, et al. Deficiency of carboxylesterase 1/esterase-x results in obesity, hepatic steatosis, and hyperlipidemia. Hepatology (Baltimore, Md). 2012;56:2188–2198.CrossRefGoogle Scholar
  19. 19.
    Xu J, Yin L, Xu Y, et al. Hepatic carboxylesterase 1 is induced by glucose and regulates postprandial glucose levels. PLoS ONE. 2014;9:e109663.CrossRefGoogle Scholar
  20. 20.
    Zhao B, Song J, St Clair RW, Ghosh S. Stable overexpression of human macrophage cholesteryl ester hydrolase results in enhanced free cholesterol efflux from human THP1 macrophages. Am J Physiol Cell Physiol. 2007;292:C405–C412.CrossRefGoogle Scholar
  21. 21.
    Ghosh S, St Clair RW, Rudel LL. Mobilization of cytoplasmic CE droplets by overexpression of human macrophage cholesteryl ester hydrolase. J Lipid Res. 2003;44:1833–1840.CrossRefGoogle Scholar
  22. 22.
    Li J, Wang Y, Matye DJ, et al. Sortilin 1 modulates hepatic cholesterol lipotoxicity in mice via functional interaction with liver carboxylesterase 1. J Biol Chem. 2017;292:146–160.CrossRefGoogle Scholar
  23. 23.
    Sapiro JM, Mashek MT, Greenberg AS, Mashek DG. Hepatic triacylglycerol hydrolysis regulates peroxisome proliferator-activated receptor alpha activity. J Lipid Res. 2009;50:1621–1629.CrossRefGoogle Scholar
  24. 24.
    Gonzalez FJ, Shah YM. PPARalpha: mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators. Toxicology. 2008;246:2–8.CrossRefGoogle Scholar
  25. 25.
    Ip E, Farrell GC, Robertson G, Hall P, Kirsch R, Leclercq I. Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice. Hepatology (Baltimore, Md). 2003;38:123–132.CrossRefGoogle Scholar
  26. 26.
    Brown MS, Goldstein JL. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci USA. 1999;96:11041–11048.CrossRefGoogle Scholar
  27. 27.
    Foufelle F, Ferre P. New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c. Biochem J. 2002;366:377–391.CrossRefGoogle Scholar
  28. 28.
    Aldridge WN. The esterases: perspectives and problems. Chem Biol Interact. 1993;87:5–13.CrossRefGoogle Scholar
  29. 29.
    Brigelius-Flohe R. Vitamin E and drug metabolism. Biochem Biophys Res Commun. 2003;305:737–740.CrossRefGoogle Scholar
  30. 30.
    Shi D, Yang J, Yang D, Yan B. Dexamethasone suppresses the expression of multiple rat carboxylesterases through transcriptional repression: evidence for an involvement of the glucocorticoid receptor. Toxicology. 2008;254:97–105.CrossRefGoogle Scholar
  31. 31.
    Xu JS, Xu Y, Li YY, et al. Carboxylesterase 1 is regulated by hepatocyte nuclear factor 4 alpha and protects against alcohol- and MCD diet-induced liver injury. Sci Rep. 2016;6:24277.CrossRefGoogle Scholar
  32. 32.
    Zhang Y, Cheng X, Aleksunes L, Klaassen CD. Transcription factor-mediated regulation of carboxylesterase enzymes in livers of mice. Drug Metab Dispos. 2012;40:1191–1197.CrossRefGoogle Scholar
  33. 33.
    Chen Y-T, Shi D, Yang D, Yan B. Antioxidant sulforaphane and sensitizer trinitrobenzene sulfonate induce carboxylesterase-1 through a novel element transactivated by nuclear factor-E2 related factor-2. Biochem Pharmacol. 2012;84:864–871.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Wenxi He
    • 1
  • Yanjiao Xu
    • 1
  • Xiuhua Ren
    • 1
  • Dong Xiang
    • 1
  • Kai Lei
    • 1
  • Chengliang Zhang
    • 1
  • Dong Liu
    • 1
    Email author
  1. 1.Department of Pharmacy, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

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