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23-05-2023 | Original Contribution

Aerobic exercise and vitamin E improve high-fat diet-induced NAFLD in rats by regulating the AMPK pathway and oxidative stress

Authors: Yaowei Bai, Tongqiang Li, Jiacheng Liu, Yingliang Wang, Chaoyang Wang, Shuguang Ju, Chen Zhou, Yang Chen, Wei Yao, Bin Xiong

Published in: European Journal of Nutrition | Issue 6/2023

Abstract

Background and aims

Non-alcoholic fatty liver disease (NAFLD) has emerged as a major chronic liver disease. We explored simple and effective ways to improve NAFLD and investigate the mechanism of action.

Methods

NAFLD was induced in 40 rats fed a high-fat diet (HFD). Magnetic resonance imaging was used to evaluate the progression and improvement of NAFLD. The treatment-related interventions included aerobic exercise (E) and vitamin E (VE) supplementation. Expression levels of proteins related to fat metabolism were also assessed. The activities of antioxidant enzymes in the liver and serum lipid metabolism were analyzed using biochemical methods.

Results

Aerobic exercise and vitamin E effectively improved NAFLD in rats, resulting in decreased hepatic fat accumulation, reduced hepatocyte ballooning, and decreased triglyceride levels. Combination therapy achieved the best effect. Both aerobic exercise and vitamin E activate the AMPK pathway to phosphorylate acetyl-CoA carboxylase (ACC) and reduce fatty acid synthesis. The expression of sterol regulatory element-binding protein-1 (SREBP-1) was decreased significantly in the treated groups, particularly in the E + VE + HFD group. The expression of carnitine palmitoyl-transferase 1C (CPT1C) significantly increased in the treated groups, particularly in the E + VE + HFD group. Compared with the control group, reactive oxygen species (ROS) in the E + HFD group were slightly decreased, while that in the VE + HFD group were significantly decreased, with the even greater reduction observed in the E + VE + HFD group.

Conclusion

Aerobic exercise and vitamin E supplementation can improve HFD-induced NAFLD in rats by regulating the AMPK pathway and reducing oxidative stress.

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Eslam M, Valenti L, Romeo S (2018) Genetics and epigenetics of NAFLD and NASH: clinical impact. J Hepatol 68(2):268–279. https://doi.org/10.1016/j.jhep.2017.09.003CrossRefPubMed

Zhou J, Zhou F, Wang W, Zhang X-J, Ji Y-X, Zhang P, She Z-G, Zhu L, Cai J, Li H (2020) Epidemiological features of NAFLD From 1999 to 2018 in China. Hepatology (Baltimore, MD) 71(5):1851–1864. https://doi.org/10.1002/hep.31150CrossRefPubMed

Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ (2018) Mechanisms of NAFLD development and therapeutic strategies. Nat Med 24(7):908–922. https://doi.org/10.1038/s41591-018-0104-9CrossRefPubMedPubMedCentral

European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO) (2016) EASL-EASD-EASO Clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 64(6):1388–1402. https://doi.org/10.1016/j.jhep.2015.11.004CrossRef

Zou T-T, Zhang C, Zhou Y-F, Han Y-J, Xiong J-J, Wu X-X, Chen Y-P, Zheng M-H (2018) Lifestyle interventions for patients with nonalcoholic fatty liver disease: a network meta-analysis. Eur J Gastroenterol Hepatol 30(7):747–755. https://doi.org/10.1097/MEG.0000000000001135CrossRefPubMed

Paris T, George ES, Roberts SK, Tierney AC (2017) The effects of diet and lifestyle interventions on insulin resistance in patients with nonalcoholic fatty liver disease: a systematic review. Eur J Gastroenterol Hepatol 29(8):867–878. https://doi.org/10.1097/MEG.0000000000000890CrossRefPubMed

Stine JG, DiJoseph K, Pattison Z, Harrington A, Chinchilli VM, Schmitz KH, Loomba R (2022) Exercise training is associated with treatment response in liver fat content by magnetic resonance imaging independent of clinically significant body weight loss in patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Am J Gastroenterol. https://doi.org/10.14309/ajg.0000000000002098CrossRefPubMed

Cho J, Johnson BD, Watt KD, Niven AS, Yeo D, Kim C-H (2022) Exercise training attenuates pulmonary inflammation and mitochondrial dysfunction in a mouse model of high-fat high-carbohydrate-induced NAFLD. BMC Med 20(1):429. https://doi.org/10.1186/s12916-022-02629-1CrossRefPubMedPubMedCentral

Henry A, Paik JM, Austin P, Eberly KE, Golabi P, Younossi I, Henry L, Gerber L, Younossi ZM (2023) Vigorous physical activity provides protection against all-cause deaths among adults patients with nonalcoholic fatty liver disease (NAFLD). Aliment Pharmacol Ther 57(6):709–722. https://doi.org/10.1111/apt.17308CrossRefPubMed

10.

Roberts LJ, Oates JA, Linton MF, Fazio S, Meador BP, Gross MD, Shyr Y, Morrow JD (2007) The relationship between dose of vitamin E and suppression of oxidative stress in humans. Free Radical Biol Med 43(10):1388–1393CrossRef

11.

Guertin KA, Grant RK, Arnold KB, Burwell L, Hartline J, Goodman PJ, Minasian LM, Lippman SM, Klein E, Cassano PA (2016) Effect of long-term vitamin E and selenium supplementation on urine F2-isoprostanes, a biomarker of oxidative stress. Free Radical Biol Med 95:349–356. https://doi.org/10.1016/j.freeradbiomed.2016.03.010CrossRef

12.

Podszun MC, Chung J-Y, Ylaya K, Kleiner DE, Hewitt SM, Rotman Y (2020) 4-HNE immunohistochemistry and image analysis for detection of lipid peroxidation in human liver samples using vitamin E treatment in NAFLD as a proof of concept. J Histochem Cytochem 68(9):635–643. https://doi.org/10.1369/0022155420946402CrossRefPubMed

13.

Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR (2010) Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 362(18):1675–1685. https://doi.org/10.1056/NEJMoa0907929CrossRefPubMedPubMedCentral

14.

Bril F, Biernacki DM, Kalavalapalli S, Lomonaco R, Subbarayan SK, Lai J, Tio F, Suman A, Orsak BK, Hecht J, Cusi K (2019) Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 42(8):1481–1488. https://doi.org/10.2337/dc19-0167CrossRefPubMed

15.

Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, Scheimann AO, Sanyal AJ, Chalasani N, Tonascia J, Ünalp A, Clark JM, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR (2011) Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 305(16):1659–1668. https://doi.org/10.1001/jama.2011.520CrossRefPubMedPubMedCentral

16.

Vilar-Gomez E, Vuppalanchi R, Gawrieh S, Ghabril M, Saxena R, Cummings OW, Chalasani N (2020) Vitamin E improves transplant-free survival and hepatic decompensation among patients with nonalcoholic steatohepatitis and advanced fibrosis. Hepatology (Baltimore, MD) 71(2):495–509. https://doi.org/10.1002/hep.30368CrossRefPubMed

17.

Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ (2018) The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 67(1):328–357. https://doi.org/10.1002/hep.29367CrossRefPubMed

18.

Romero-Gómez M, Zelber-Sagi S, Trenell M (2017) Treatment of NAFLD with diet, physical activity and exercise. J Hepatol 67(4):829–846. https://doi.org/10.1016/j.jhep.2017.05.016CrossRefPubMed

19.

Stavropoulos K, Imprialos K, Pittaras A, Faselis C, Narayan P, Kokkinos P (2018) Lifestyle modifications in non-alcoholic fatty liver disease and non- alcoholic steatohepatitis. Curr Vasc Pharmacol 16(3):239–245. https://doi.org/10.2174/1570161115666170621080835CrossRefPubMed

20.

Schultz A, Mendonca LS, Aguila MB, Mandarim-de-Lacerda CA (2012) Swimming training beneficial effects in a mice model of nonalcoholic fatty liver disease. Exp Toxicol Pathol 64(4):273–282. https://doi.org/10.1016/j.etp.2010.08.019CrossRefPubMed

21.

Muñoz P, Munné-Bosch S (2019) Vitamin E in plants: biosynthesis, transport, and function. Trends Plant Sci 24(11):1040–1051. https://doi.org/10.1016/j.tplants.2019.08.006CrossRefPubMed

22.

Raso GM, Esposito E, Iacono A, Pacilio M, Cuzzocrea S, Canani RB, Calignano A, Meli R (2009) Comparative therapeutic effects of metformin and vitamin E in a model of non-alcoholic steatohepatitis in the young rat. Eur J Pharmacol 604(1–3):125–131. https://doi.org/10.1016/j.ejphar.2008.12.013CrossRefPubMed

23.

Nguyen G, Park SY, Le CT, Park WS, Choi DH, Cho E-H (2018) Metformin ameliorates activation of hepatic stellate cells and hepatic fibrosis by succinate and GPR91 inhibition. Biochem Biophys Res Commun 495(4):2649–2656. https://doi.org/10.1016/j.bbrc.2017.12.143CrossRefPubMed

24.

Podszun MC, Frank J (2021) Impact of vitamin E on redox biomarkers in non-alcoholic fatty liver disease. Redox Biol 42:101937. https://doi.org/10.1016/j.redox.2021.101937CrossRefPubMedPubMedCentral

25.

Qian X, Wang T, Gong J, Wang L, Chen X, Lin H, Tu W, Jiang S, Li S (2021) Exercise in mice ameliorates high-fat diet-induced nonalcoholic fatty liver disease by lowering HMGCS2. Aging 13(6):8960–8974. https://doi.org/10.18632/aging.202717CrossRefPubMedPubMedCentral

26.

Buzzetti E, Pinzani M, Tsochatzis EA (2016) The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 65(8):1038–1048. https://doi.org/10.1016/j.metabol.2015.12.012CrossRefPubMed

27.

Marchisello S, Di Pino A, Scicali R, Urbano F, Piro S, Purrello F, Rabuazzo AM (2019) Pathophysiological, molecular and therapeutic issues of nonalcoholic fatty liver disease: an overview. Int J Mol Sci 20:8. https://doi.org/10.3390/ijms20081948CrossRef

28.

Zhao P, Sun X, Chaggan C, Liao Z, In Wong K, He F, Singh S, Loomba R, Karin M, Witztum JL, Saltiel AR (2020) An AMPK-caspase-6 axis controls liver damage in nonalcoholic steatohepatitis. Science 367(6478):652–660. https://doi.org/10.1126/science.aay0542CrossRefPubMedPubMedCentral

29.

Day EA, Ford RJ, Steinberg GR (2017) AMPK as a therapeutic target for treating metabolic diseases. Trends Endocrinol Metab 28(8):545–560. https://doi.org/10.1016/j.tem.2017.05.004CrossRefPubMed

30.

Garcia D, Hellberg K, Chaix A, Wallace M, Herzig S, Badur MG, Lin T, Shokhirev MN, Pinto AFM, Ross DS, Saghatelian A, Panda S, Dow LE, Metallo CM, Shaw RJ (2019) Genetic liver-specific AMPK activation protects against diet-induced obesity and NAFLD. Cell Rep 26(1):192-208.e196. https://doi.org/10.1016/j.celrep.2018.12.036CrossRefPubMedPubMedCentral

31.

Zhu X, Bian H, Wang L, Sun X, Xu X, Yan H, Xia M, Chang X, Lu Y, Li Y, Xia P, Li X, Gao X (2019) Berberine attenuates nonalcoholic hepatic steatosis through the AMPK-SREBP-1c-SCD1 pathway. Free Radical Biol Med 141:192–204. https://doi.org/10.1016/j.freeradbiomed.2019.06.019CrossRef

32.

Diniz TA, de Lima Junior EA, Teixeira AA, Biondo LA, da Rocha LAF, Valadão IC, Silveira LS, Cabral-Santos C, de Souza CO, Rosa Neto JC (2021) Aerobic training improves NAFLD markers and insulin resistance through AMPK-PPAR-α signaling in obese mice. Life Sci 266:118868. https://doi.org/10.1016/j.lfs.2020.118868CrossRefPubMed

33.

Sekiya M, Hiraishi A, Touyama M, Sakamoto K (2008) Oxidative stress induced lipid accumulation via SREBP1c activation in HepG2 cells. Biochem Biophys Res Commun 375(4):602–607. https://doi.org/10.1016/j.bbrc.2008.08.068CrossRefPubMed

34.

Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JYJ, Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M (2011) AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 13(4):376–388. https://doi.org/10.1016/j.cmet.2011.03.009CrossRefPubMedPubMedCentral

35.

Thomas DT, DelCimmuto NR, Flack KD, Stec DE, Hinds TD (2022) Reactive oxygen species (ROS) and antioxidants as immunomodulators in exercise: implications for heme oxygenase and bilirubin. Antioxidants (Basel). https://doi.org/10.3390/antiox11020179CrossRefPubMedPubMedCentral

36.

Gehrke N, Biedenbach J, Huber Y, Straub BK, Galle PR, Simon P, Schattenberg JM (2019) Voluntary exercise in mice fed an obesogenic diet alters the hepatic immune phenotype and improves metabolic parameters - an animal model of life style intervention in NAFLD. Sci Rep 9(1):4007. https://doi.org/10.1038/s41598-018-38321-9CrossRefPubMedPubMedCentral

37.

Cintra DE, Ropelle ER, Vitto MF, Luciano TF, Souza DR, Engelmann J, Marques SO, Lira FS, de Pinho RA, Pauli JR, De Souza CT (2018) Retraction notice to “Reversion of hepatic steatosis by exercise training in obese mice: the role of sterol regulatory element-binding protein-1c” [Life Sci. Title 91/11-12 (2012) 395-401]. Life Sci 193:309. https://doi.org/10.1016/j.lfs.2017.12.028CrossRefPubMed

38.

Hannukainen JC, Nuutila P, Borra R, Ronald B, Kaprio J, Kujala UM, Janatuinen T, Heinonen OJ, Kapanen J, Viljanen T, Haaparanta M, Rönnemaa T, Parkkola R, Knuuti J, Kalliokoski KK (2007) Increased physical activity decreases hepatic free fatty acid uptake: a study in human monozygotic twins. J Physiol 578(Pt 1):347–358CrossRefPubMed

39.

Thiele JJ, Ekanayake-Mudiyanselage S (2007) Vitamin E in human skin: organ-specific physiology and considerations for its use in dermatology. Mol Aspects Med 28(5–6):646–667. https://doi.org/10.1016/j.mam.2007.06.001CrossRefPubMed

40.

Zhao Q, Liu J, Deng H, Ma R, Liao JY, Liang H, Hu J, Li J, Guo Z, Cai J, Xu X, Gao Z, Su S (2020) Targeting mitochondria-located circRNA SCAR alleviates NASH via reducing mROS output. Cell 183(1):76-93.e22. https://doi.org/10.1016/j.cell.2020.08.009CrossRefPubMed

41.

Chen Z, Tian R, She Z, Cai J, Li H (2020) Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease. Free Radic Biol Med 152:116–141. https://doi.org/10.1016/j.freeradbiomed.2020.02.025CrossRefPubMed

42.

Świderska M, Maciejczyk M, Zalewska A, Pogorzelska J, Flisiak R, Chabowski A (2019) Oxidative stress biomarkers in the serum and plasma of patients with non-alcoholic fatty liver disease (NAFLD). Can plasma AGE be a marker of NAFLD? Oxidative stress biomarkers in NAFLD patients. Free Radic Res 53(8):841–850. https://doi.org/10.1080/10715762.2019.1635691CrossRefPubMed

43.

Yesilova Z, Yaman H, Oktenli C, Ozcan A, Uygun A, Cakir E, Sanisoglu SY, Erdil A, Ates Y, Aslan M, Musabak U, Erbil MK, Karaeren N, Dagalp K (2005) Systemic markers of lipid peroxidation and antioxidants in patients with nonalcoholic fatty liver disease. Am J Gastroenterol 100(4):850–855. https://doi.org/10.1111/j.1572-0241.2005.41500.xCrossRefPubMed

44.

Preziosi ME, Singh S, Valore EV, Jung G, Popovic B, Poddar M, Nagarajan S, Ganz T, Monga SP (2017) Mice lacking liver-specific β-catenin develop steatohepatitis and fibrosis after iron overload. J Hepatol 67(2):360–369. https://doi.org/10.1016/j.jhep.2017.03.012CrossRefPubMedPubMedCentral

45.

Podszun MC, Alawad AS, Lingala S, Morris N, Huang W-CA, Yang S, Schoenfeld M, Rolt A, Ouwerkerk R, Valdez K, Umarova R, Ma Y, Fatima SZ, Lin DD, Mahajan LS, Samala N, Violet P-C, Levine M, Shamburek R, Gharib AM, Kleiner DE, Garraffo HM, Cai H, Walter PJ, Rotman Y (2020) Vitamin E treatment in NAFLD patients demonstrates that oxidative stress drives steatosis through upregulation of de-novo lipogenesis. Redox Biol 37:101710. https://doi.org/10.1016/j.redox.2020.101710CrossRefPubMedPubMedCentral

46.

Semmler G, Datz C, Reiberger T, Trauner M (2021) Diet and exercise in NAFLD/NASH: beyond the obvious. Liver Int 41(10):2249–2268. https://doi.org/10.1111/liv.15024CrossRefPubMedPubMedCentral

47.

Farzanegi P, Dana A, Ebrahimpoor Z, Asadi M, Azarbayjani MA (2019) Mechanisms of beneficial effects of exercise training on non-alcoholic fatty liver disease (NAFLD): Roles of oxidative stress and inflammation. Eur J Sport Sci 19(7):994–1003. https://doi.org/10.1080/17461391.2019.1571114CrossRefPubMed

48.

Miyazawa T, Burdeos GC, Itaya M, Nakagawa K, Miyazawa T (2019) Vitamin E: regulatory redox interactions. IUBMB Life 71(4):430–441. https://doi.org/10.1002/iub.2008CrossRefPubMed

49.

Mustacich DJ, Bruno RS, Traber MG (2007) Vitamin E. Vitam Horm 76:1–21. https://doi.org/10.1016/s0083-6729(07)76001-6CrossRefPubMed

Title: Aerobic exercise and vitamin E improve high-fat diet-induced NAFLD in rats by regulating the AMPK pathway and oxidative stress
Authors: Yaowei Bai
Tongqiang Li
Jiacheng Liu
Yingliang Wang
Chaoyang Wang
Shuguang Ju
Chen Zhou
Yang Chen
Wei Yao
Bin Xiong
Publication date: 23-05-2023
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Nutrition / Issue 6/2023
Print ISSN: 1436-6207
Electronic ISSN: 1436-6215
DOI: https://doi.org/10.1007/s00394-023-03179-9

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