Reduced Oxidative Stress and Enhanced FGF21 Formation in Livers of Endurance-Exercised Rats with Diet-Induced NASH
Abstract
:1. Introduction
2. Materials and Methods
3. Results
3.1. Exercise-Dependent Attenuation of Diet-Induced Glucose Intolerance
3.2. Exercise-Dependent Increase in Diet-Induced Hepatic Inflammatory Response
3.3. Exercise-Dependent Reduction of Diet-Induced Hepatic Cholesterol Overload and Oxidative Stress
3.4. Possible Contribution of Exercise-Dependent Hepatic FGF21 Production to the Reduction of Diet-Induced Systemic Glucose Intolerance
4. Discussion
4.1. Exercise-Dependent Augmentation of Hepatic Inflammation
4.2. Impact of Exercise on Severe Oxidative Stress in Liver
4.3. Impact of Exercise on Glucose Tolerance
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Younossi, Z.M.; Koenig, A.B.; Abdelatif, D.; Fazel, Y.; Henry, L.; Wymer, M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016, 64, 73–84. [Google Scholar] [CrossRef] [PubMed]
- Younossi, Z.M.; Golabi, P.; de Avila, L.; Paik, J.M.; Srishord, M.; Fukui, N.; Qiu, Y.; Burns, L.; Afendy, A.; Nader, F. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J. Hepatol. 2019, 71, 793–801. [Google Scholar] [CrossRef] [PubMed]
- Petäjä, E.M.; Yki-Järvinen, H. Definitions of Normal Liver Fat and the Association of Insulin Sensitivity with Acquired and Genetic NAFLD-A Systematic Review. Int. J. Mol. Sci. 2016, 17, 633. [Google Scholar] [CrossRef] [PubMed]
- Golabi, P.; Bush, H.; Younossi, Z.M. Treatment Strategies for Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Clin. Liver Dis. 2017, 21, 739–753. [Google Scholar] [CrossRef]
- Francque, S.; Vonghia, L. Pharmacological Treatment for Non-alcoholic Fatty Liver Disease. Adv. Ther. 2019, 36, 1052–1074. [Google Scholar] [CrossRef] [Green Version]
- Van der Windt, D.J.; Sud, V.; Zhang, H.; Tsung, A.; Huang, H. The Effects of Physical Exercise on Fatty Liver Disease. Gene Expr. 2018, 18, 89–101. [Google Scholar] [CrossRef] [Green Version]
- Pugh, C.J.A.; Cuthbertson, D.J.; Sprung, V.S.; Kemp, G.J.; Richardson, P.; Umpleby, A.M.; Green, D.J.; Cable, N.T.; Jones, H. Exercise training improves cutaneous microvascular function in nonalcoholic fatty liver disease. Am. J. Physiol. Endocrinol. Metab. 2013, 305, 8. [Google Scholar] [CrossRef]
- Pugh, C.J.A.; Spring, V.S.; Kemp, G.J.; Richardson, P.; Shojaee-Moradie, F.; Umpleby, A.M.; Green, D.J.; Cable, N.T.; Jones, H.; Cuthbertson, D.J. Exercise training reverses endothelial dysfunction in nonalcoholic fatty liver disease. Am. J. Physiol. Heart Circ. Physiol. 2014, 307, 306. [Google Scholar] [CrossRef]
- Hansen, H.H.; Feigh, M.; Veidal, S.S.; Rigbolt, K.T.; Vrang, N.; Fosgerau, K. Mouse models of nonalcoholic steatohepatitis in preclinical drug development. Drug Discov. Today 2017, 22, 1707–1718. [Google Scholar] [CrossRef]
- Sanches, S.C.L.; Ramalho, L.N.Z.; Augusto, M.J.; da Silva, D.M.; Ramalho, F.S. Nonalcoholic Steatohepatitis: A Search for Factual Animal Models. Biomed Res. Int. 2015, 2015, 574832. [Google Scholar] [CrossRef]
- Jahn, D.; Kircher, S.; Hermanns, H.M.; Geier, A. Animal models of NAFLD from a hepatologist’s point of view. Biochim. Biophys. Acta Mol. Basis Dis. 2019, 1865, 943–953. [Google Scholar] [CrossRef] [PubMed]
- Lira, F.S.; Tavares, F.L.; Yamashita, A.S.; Koyama, C.H.; Alves, M.J.; Caperuto, E.C.; Batista, M.L.; Seelaender, M. Effect of endurance training upon lipid metabolism in the liver of cachectic tumour-bearing rats. Cell Biochem. Funct. 2008, 26, 701–708. [Google Scholar] [CrossRef] [PubMed]
- Kleiner, D.E.; Brunt, E.M.; van Natta, M.; Behling, C.; Contos, M.J.; Cummings, O.W.; Ferrell, L.D.; Liu, Y.-C.; Torbenson, M.S.; Unalp-Arida, A.; et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005, 41, 1313–1321. [Google Scholar] [CrossRef] [PubMed]
- Liang, W.; Menke, A.L.; Driessen, A.; Koek, G.H.; Lindeman, J.H.; Stoop, R.; Havekes, L.M.; Kleemann, R.; van den Hoek, A.M. Establishment of a general NAFLD scoring system for rodent models and comparison to human liver pathology. PLoS ONE 2014, 9, e115922. [Google Scholar] [CrossRef] [PubMed]
- Henkel, J.; Coleman, C.D.; Schraplau, A.; Jöhrens, K.; Weiss, T.S.; Jonas, W.; Schürmann, A.; Püschel, G.P. Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model. Sci. Rep. 2018, 8, 16127. [Google Scholar] [CrossRef] [PubMed]
- Henkel, J.; Alfine, E.; Saín, J.; Jöhrens, K.; Weber, D.; Castro, J.P.; König, J.; Stuhlmann, C.; Vahrenbrink, M.; Jonas, W.; et al. Soybean Oil-Derived Poly-Unsaturated Fatty Acids Enhance Liver Damage in NAFLD Induced by Dietary Cholesterol. Nutrients 2018, 10, 1326. [Google Scholar] [CrossRef]
- Henkel, J.; Neuschäfer-Rube, F.; Pathe-Neuschäfer-Rube, A.; Püschel, G.P. Aggravation by prostaglandin E2 of interleukin-6-dependent insulin resistance in hepatocytes. Hepatology 2009, 50, 781–790. [Google Scholar] [CrossRef]
- Henkel, J.; Coleman, C.D.; Schraplau, A.; Jӧhrens, K.; Weber, D.; Castro, J.P.; Hugo, M.; Schulz, T.J.; Krämer, S.; Schürmann, A.; et al. Induction of steatohepatitis (NASH) with insulin resistance in wildtype B6 mice by a western-type diet containing soybean oil and cholesterol. Mol. Med. 2017, 23, 70–82. [Google Scholar] [CrossRef]
- Brigelius-Flohé, R.; Wingler, K.; Müller, C. Estimation of individual types of glutathione peroxidases. Meth. Enzymol. 2002, 347, 101–112. [Google Scholar] [CrossRef]
- Johnson, N.A.; Sachinwalla, T.; Walton, D.W.; Smith, K.; Armstrong, A.; Thompson, M.W.; George, J. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology 2009, 50, 1105–1112. [Google Scholar] [CrossRef]
- Laeger, T.; Baumeier, C.; Wilhelmi, I.; Würfel, J.; Kamitz, A.; Schürmann, A. FGF21 improves glucose homeostasis in an obese diabetes-prone mouse model independent of body fat changes. Diabetologia 2017, 60, 2274–2284. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- BonDurant, L.D.; Potthoff, M.J. Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis. Annu. Rev. Nutr. 2018, 38, 173–196. [Google Scholar] [CrossRef] [PubMed]
- Mashili, F.L.; Austin, R.L.; Deshmukh, A.S.; Fritz, T.; Caidahl, K.; Bergdahl, K.; Zierath, J.R.; Chibalin, A.V.; Moller, D.E.; Kharitonenkov, A.; et al. Direct effects of FGF21 on glucose uptake in human skeletal muscle: Implications for type 2 diabetes and obesity. Diabetes. Metab. Res. Rev. 2011, 27, 286–297. [Google Scholar] [CrossRef] [PubMed]
- Gómez-Sámano, M.Á.; Grajales-Gómez, M.; Zuarth-Vázquez, J.M.; Navarro-Flores, M.F.; Martínez-Saavedra, M.; Juárez-León, Ó.A.; Morales-García, M.G.; Enríquez-Estrada, V.M.; Gómez-Pérez, F.J.; Cuevas-Ramos, D. Fibroblast growth factor 21 and its novel association with oxidative stress. Redox Biol. 2017, 11, 335–341. [Google Scholar] [CrossRef]
- Hoene, M.; Franken, H.; Fritsche, L.; Lehmann, R.; Pohl, A.K.; Häring, H.U.; Zell, A.; Schleicher, E.D.; Weigert, C. Activation of the mitogen-activated protein kinase (MAPK) signalling pathway in the liver of mice is related to plasma glucose levels after acute exercise. Diabetologia 2010, 53, 1131–1141. [Google Scholar] [CrossRef] [Green Version]
- Da Rocha, A.L.; Pinto, A.P.; Kohama, E.B.; Pauli, J.R.; de Moura, L.P.; Cintra, D.E.; Ropelle, E.R.; da Silva, A.S. The proinflammatory effects of chronic excessive exercise. Cytokine 2019, 119, 57–61. [Google Scholar] [CrossRef]
- Smith, L.L. Cytokine hypothesis of overtraining: A physiological adaptation to excessive stress? Med. Sci. Sports Exerc. 2000, 32, 317–331. [Google Scholar] [CrossRef]
- Lira, F.S.; Yamashita, A.S.; Rosa, J.C.; Koyama, C.H.; Caperuto, E.C.; Batista, M.L.; Seelaender, M.C.L. Exercise training decreases adipose tissue inflammation in cachectic rats. Horm. Metab. Res. 2012, 44, 91–98. [Google Scholar] [CrossRef]
- Passos, E.; Pereira, C.D.; Gonçalves, I.O.; Rocha-Rodrigues, S.; Silva, N.; Guimarães, J.T.; Neves, D.; Ascensão, A.; Magalhães, J.; Martins, M.J. Role of physical exercise on hepatic insulin, glucocorticoid and inflammatory signaling pathways in an animal model of non-alcoholic steatohepatitis. Life Sci. 2015, 123, 51–60. [Google Scholar] [CrossRef]
- Nuño-Lámbarri, N.; Domínguez-Pérez, M.; Baulies-Domenech, A.; Monte, M.J.; Marin, J.J.G.; Rosales-Cruz, P.; Souza, V.; Miranda, R.U.; Bucio, L.; Montalvo-Jave, E.E.; et al. Liver Cholesterol Overload Aggravates Obstructive Cholestasis by Inducing Oxidative Stress and Premature Death in Mice. Oxid. Med. Cell. Longev. 2016, 2016, 9895176. [Google Scholar] [CrossRef]
- Huo, B.; Dossing, D.A.; Dimuzio, M.T. Generation and characterization of a human osteosarcoma cell line stably transfected with the human estrogen receptor gene. J. Bone Miner. Res. 1995, 10, 769–781. [Google Scholar] [CrossRef] [PubMed]
- Bellanti, F.; Mitarotonda, D.; Tamborra, R.; Blonda, M.; Iannelli, G.; Petrella, A.; Sanginario, V.; Iuliano, L.; Vendemiale, G.; Serviddio, G. Oxysterols induce mitochondrial impairment and hepatocellular toxicity in non-alcoholic fatty liver disease. Free Radic. Biol. Med. 2014, 75 (Suppl. 1), 7. [Google Scholar] [CrossRef] [PubMed]
- Farzanegi, P.; Dana, A.; Ebrahimpoor, Z.; Asadi, M.; Azarbayjani, M.A. Mechanisms of beneficial effects of exercise training on non-alcoholic fatty liver disease (NAFLD): Roles of oxidative stress and inflammation. Eur. J. Sport Sci. 2019, 19, 994–1003. [Google Scholar] [CrossRef] [PubMed]
- Weigert, C.; Hoene, M.; Plomgaard, P. Hepatokines-a novel group of exercise factors. Pflugers Arch. 2019, 471, 383–396. [Google Scholar] [CrossRef] [PubMed]
- Ennequin, G.; Sirvent, P.; Whitham, M. Role of exercise-induced hepatokines in metabolic disorders. Am. J. Physiol. Endocrinol. Metab. 2019, 317, E11–E24. [Google Scholar] [CrossRef] [PubMed]
- Camporez, J.P.G.; Jornayvaz, F.R.; Petersen, M.C.; Pesta, D.; Guigni, B.A.; Serr, J.; Zhang, D.; Kahn, M.; Samuel, V.T.; Jurczak, M.J.; et al. Cellular mechanisms by which FGF21 improves insulin sensitivity in male mice. Endocrinology 2013, 154, 3099–3109. [Google Scholar] [CrossRef]
- Lee, M.S.; Choi, S.-E.; Ha, E.S.; An, S.-Y.; Kim, T.H.; Han, S.J.; Kim, H.J.; Kim, D.J.; Kang, Y.; Lee, K.-W. Fibroblast growth factor-21 protects human skeletal muscle myotubes from palmitate-induced insulin resistance by inhibiting stress kinase and NF-κB. Metab. Clin. Exp. 2012, 61, 1142–1151. [Google Scholar] [CrossRef]
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Henkel, J.; Buchheim-Dieckow, K.; Castro, J.P.; Laeger, T.; Wardelmann, K.; Kleinridders, A.; Jöhrens, K.; Püschel, G.P. Reduced Oxidative Stress and Enhanced FGF21 Formation in Livers of Endurance-Exercised Rats with Diet-Induced NASH. Nutrients 2019, 11, 2709. https://doi.org/10.3390/nu11112709
Henkel J, Buchheim-Dieckow K, Castro JP, Laeger T, Wardelmann K, Kleinridders A, Jöhrens K, Püschel GP. Reduced Oxidative Stress and Enhanced FGF21 Formation in Livers of Endurance-Exercised Rats with Diet-Induced NASH. Nutrients. 2019; 11(11):2709. https://doi.org/10.3390/nu11112709
Chicago/Turabian StyleHenkel, Janin, Katja Buchheim-Dieckow, José P. Castro, Thomas Laeger, Kristina Wardelmann, André Kleinridders, Korinna Jöhrens, and Gerhard P. Püschel. 2019. "Reduced Oxidative Stress and Enhanced FGF21 Formation in Livers of Endurance-Exercised Rats with Diet-Induced NASH" Nutrients 11, no. 11: 2709. https://doi.org/10.3390/nu11112709