نوع مقاله : مقاله پژوهشی

نویسندگان

1 دانشجوی دوره دکترای فیزیولوژی ورزشی، دانشکده تربیت بدنی و علوم ورزشی، دانشگاه گیلان، رشت، ایران.

2 استاد گروه فیزیولوژی ورزشی، دانشکده تربیت بدنی و علوم ورزشی، دانشگاه گیلان، رشت، ایران.

3 دانشیار گروه بیوشیمی، دانشکده علوم، دانشگاه گیلان، رشت، ایران.

4 استادیار گروه بیوتکنولوژی کشاورزی، دانشکده کشاورزی، دانشگاه گیلان، رشت، ایران.

چکیده

زمینـه و هـدف: بررسی شکل‌‌گیری و تجزیه لیپیدها در پاسخ به محرک‌‌های تغذیه‌‌ای و تمرینی، می‌‌تواند دیدگاه بهتری را نسبت به استراتژی پیشگیری و درمان کبد چرب غیرالکلی فراهم نماید. بنابراین، هدف از این مطالعه بررسی اثر تغذیه، تمرین و هیپوکسی بر مکانیسم‌‌های مولکولی فرآیند متابولیسم چربی کبد می‌‌باشد. روش تحقیق: تعداد 24 سر رت نر نژاد ویستار با سن تقریبی پنج هفته و میانگین وزن 9/94±165/90 گرم، به طور تصادفی به چهار گروه شامل رژیم غذایی نرمال (ND)، رژیم غذایی پرچرب (HFD)، رژیم غذایی پرچرب+تمرین در حالت نرموکسی (HFD+NE)، و رژیم غذایی پرچرب+تمرین در حالت هیپوکسی (HFD+HE) تقسیم شدند. پس از تعیین حداکثر سرعت هوازی (MAV)  در شرایط نرموکسی (ارتفاع  ̴ 50 متر) و هیپوکسی - هیپو باریک (ارتفاع ̴ 3000 متر)، تمرینات با شدتی معادل 68 تا 80 درصد MAV به مدت 12 هفته و تکرار سه جلسه در هفته، با رعایت اصل اضافه‌بار اجرا شدند. در پایان، نمونه‌‌های بافتی برای اندازه‌‌گیری تغییرات بیان ژن‌‌های Srebf1 ،Chreb و Atgl جمع‌‌آوری شد. بیان ژن‌ها با استفاده از روش Real-Time PCR اندازه‌‌گیری شد. داده‌‌ها با استفاده از آزمون‌‌های تحلیل واریانس و توکی در سطح معنی‌‌داری 0/05>p تجزیه ‌و تحلیل شدند. یافته‌‌ها: در تمامی گروه‌‌های دارای HFD، محتوای چربی کبدی و بیان ژن‌‌های Srebf1 و Chreb نسبت به گروه ND، افزایش داشت. میزان افزایش بیان ژن Srebf1 و Chreb در گروه HFD+HE نسبت به سایر گروه‌‌ها بیشتر بود؛ اما بیان ژن Atgl در گروه HFD نسبت به دیگر گروه‌‌ها، پایین‌‌تر بود. نتیجه‌‌گیری: به نظر می‌‌رسد HFD با افزایش لیپوژنز و کاهش لیپولیز، سبب افزایش محتوای چربی کبدی می‌‌شود. احتمالاً تمرین از طریق افزایش بیان ژن‌‌های لیپولیزی، میزان افزایش محتوای چربی کبد در رت‌‌های دارای HFD را تا حدودی کنترل می‌‌کند؛ اما در تغییر بیان ژن‌‌های لیپوژنزی نسبت به تغذیه، نقش کمتری دارد. به‌طورکلی تمرین در شرایط هیپوکسی، تأثیر مازادی بر کاهش محتوای چربی کبدی ندرد.

کلیدواژه‌ها

عنوان مقاله [English]

The effect of aerobic training in hypoxia and normoxia conditions on the signaling pathway of lipogenesis and lipolysis in the liver of male rats fed a high-fat diet

نویسندگان [English]

  • Seyed Morteza Hosseini 1
  • Hamid Mohebbi 2
  • Hossein Ghafoori 3
  • Mohammad Hosseine Rezadoost 4

1 PhD Student in Exercise Physiology, Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, University of Guilan, Rasht, Iran.

2 Professor at Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, University of Guilan, Rasht, Iran.

3 Associate Professor at Department of Biochemistry, Faculty of Sciences, University of Guilan, Rasht, Iran.

4 Assistant Professor at Department of Biotechnology, Faculty of Agricultural Sciences, University of Guilan, Rasht, Iran.

چکیده [English]

Background and Aim: The study of lipid formation and degradation in response to dietary and exercise stimuli may provide a better perspective for preventing and treating nonalcoholic fatty liver disease. Therefore, this study aims to investigate the effects of diet, exercise, and hypoxia on the molecular mechanisms related to lipid metabolism. Materials and Methods: A total of twenty-four male Wistar rats aged approximately five weeks with an average weight of 165.9±9.94 grams were randomly divided into four groups including normal diet (ND), high-fat diet (HFD), high-fat diet+exercise in normoxia (HFD+NE), and high-fat diet+exercise in hypoxia (HFD+HE). The maximal aerobic velocity (MAV) was determined under normoxic conditions (at an altitude of approximately 50 m) and hypoxic-hypobaric conditions (at an altitude of approximately 3000 m). Following this, considering overload, exercise sessions were conducted three times a week for a duration of 12 weeks at intensities ranging from 68 to 80 percent of MAV.  At the end, tissue samples were collected to measure changes in the expression of Srebf1, Chreb and Atgl genes. Gene expression was measured using Real-Time PCR method and data were analyzed using ANOVA and Tukey tests at a significance level of p<0.05. Results: The results showed that in all groups receiving a HFD, liver fat content and expression of Srebf1 and Chreb, genes were increased; whereas the increase in Srebf1 and Chreb was greater in the HFD+HE group than in the other groups. Moreover, Atgl gene expression was lower in the HFD group than in other groups. Conclusion: A HFD apparently increases liver fat content by increasing lipogenesis and decreasing lipolysis. Exercise is thought to regulate the increase in liver fat content in rats on HFD by increasing the expression of lipolysis genes. Training probably plays a lesser role than diet in altering lipogenic genes expression than nutrition. Hypoxic training had no additional effect on reducing liver fat content.

کلیدواژه‌ها [English]

  • Hypoxia training
  • Non-alcoholic fatty liver
  • Gene expression of Chrebp
  • Gene expression of Srebf1
  • Gene expression of Atgl
Ahmadi, A., Sheikholeslami-Vatani, D., Gaeini, S., & Baazm, M. (2021). The effects of different training modalities on monocarboxylate transporters MCT1 and MCT4, hypoxia inducible factor-1α (HIF-1α), and PGC-1α gene expression in rat skeletal muscles. Molecular Biology Reports, 48, 2153-2161. http://dx.doi.org/10.1007/s11033-021-06224-0
Angulo, P. (2002). Nonalcoholic fatty liver disease. New England Journal of Medicine, 346(16), 1221-1231. http://dx.doi.org/10.1056/nejmra011775 
Axsom, J.E., Schmidt, H.D., Matura, L.A., & Libonati, J.R. (2021). The influence of epigenetic modifications on metabolic changes in white adipose tissue and liver and their potential impact in exercise. Frontiers in Physiology, 12, 686270. http://dx.doi.org/10.3389/fphys.2021.686270 
Azuma, K., Kagi, N., Yanagi, U., & Osawa, H. (2018). Effects of low-level inhalation exposure to carbon dioxide in indoor environments: A short review on human health and psychomotor performance. Environment International, 121(Pt 1), 51-56. http://dx.doi.org/10.1016/j.envint.2018.08.059 
Baek, K.W., Gim, J.A., & Park, J.J. (2020). Regular moderate aerobic exercise improves high-fat diet-induced nonalcoholic fatty liver disease via monoacylglycerol O-acyltransferase 1 pathway suppression. Journal of Sport and Health Science, 9(5), 472-478. http://dx.doi.org/10.1016/j.jshs.2018.09.001 
Beylot, M., Neggazi, S., Hamlat, N., Langlois, D., & Forcheron, F. (2012). Perilipin 1 ablation in mice enhances lipid oxidation during exercise and does not impair exercise performance. Metabolism, 61(3), 415-423. http://dx.doi.org/10.1016/j.metabol.2011.07.019 
Brent, A. (2010). Neuschwander-tetri hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology, 52(2), 774-788. http://dx.doi.org/10.1002/hep.23719
Choi, S.M., Cho, H.J., Cho, H., Kim, K. H., Kim, J. B., & Park, H. (2008). Stra13/DEC1 and DEC2 inhibit sterol regulatory element binding protein-1c in a hypoxia-inducible factor-dependent mechanism. Nucleic Acids Research, 36(20), 6372-6385. http://dx.doi.org/10.1093/nar/gkn620 
Çolak, R., Agascıoglu, E., & Çakatay, U. (2021). “Live high train low” hypoxic training enhances exercise performance with efficient redox homeostasis in rats’ Soleus muscle. High Altitude Medicine & Biology, 22(1), 77-86. http://dx.doi.org/10.1089/ham.2020.0136 
Cunningham, C.C. (2003). Energy availability and alcohol-related liver pathology. Alcohol Research & Health, 27(4), 291. 
De Groote, E., Britto, F.A., Balan, E., Warnier, G., Thissen, J.P., Nielens, H., ... & Deldicque, L. (2021). Effect of hypoxic exercise on glucose tolerance in healthy and prediabetic adults. American Journal of Physiology-Endocrinology and Metabolism, 320(1), E43-E54. http://dx.doi.org/10.1152/ajpendo.00263.2020 
Dentin, R., Benhamed, F., Hainault, I., Fauveau, V., Foufelle, F., Dyck, J.R., ... & Postic, C. (2006). Liver-specific inhibition of ChrebP improves hepatic steatosis and insulin resistance in ob/ob mice. Diabetes, 55(8), 2159-2170. http://dx.doi.org/10.2337/db06-0200 
Ding, W.-X., Manley, S., & Ni, H.-M. (2011). The emerging role of autophagy in alcoholic liver disease. Experimental Biology and Medicine, 236(5), 546-556. http://dx.doi.org/10.1258/ebm.2011.010360 
Esteva, S., Pedret, R., Fort, N., Torrella, J. R., Pagès, T., & Viscor, G. (2010). Oxidative stress status in rats after intermittent exposure to hypobaric hypoxia.  Wilderness & Environmental Medicine, 21(4), 325-331. http://dx.doi.org/10.1016/j.wem.2010.09.004 
Faridnia, M., Mohebi, h., Khalafi, M., & Moghaddami, K. (2019). The effect of interval and continuous training on the content of perilipin 1, Atgl and CGI-58 in visceral adipose tissue of obese male rats. Scientific Journal of Kurdistan University of Medical Sciences, 24(1), 78-89. [In Persian]. http://dx.doi.org/10.29252/sjku.24.1.78 
Flores, K., Siques, P., Brito, J., Ordenes, S., Arriaza, K., Pena, E., . . . & Arribas, S. (2020). Lower body weight in rats under hypobaric hypoxia exposure would lead to reduced right ventricular hypertrophy and increased AMPK activation. Frontiers in Physiology, 11, 342. http://dx.doi.org/10.3389/fphys.2020.00342 
Fuchs, C.D., Claudel, T., & Trauner, M. (2014). Role of metabolic lipases and lipolytic metabolites in the pathogenesis of NAFLD. Trends in Endocrinology & Metabolism, 25(11), 576-585. http://dx.doi.org/10.1016/j.tem.2014.08.001 
Gamelin, F.-X., Aucouturier, J., Iannotti, F.A., Piscitelli, F., Mazzarella, E., Aveta, T., ... &  Montel, V. (2016). Effects of chronic exercise on the endocannabinoid system in Wistar rats with high-fat diet-induced obesity. Journal of Physiology and Biochemistry, 72, 183-199. http://dx.doi.org/10.1007/s13105-016-0469-5 
Gao, Y., Zhang, W., Zeng, L.Q., Bai, H., Li, J., Zhou, J., . . . & Qin, X.J. (2020). Exercise and dietary intervention ameliorate high-fat diet-induced NAFLD and liver aging by inducing lipophagy. Redox Biology, 36, 101635. http://dx.doi.org/10.1016/j.redox.2020.101635 
Gilliam, P., Spirduso, W., Martin, T., Walters, T., Wilcox, R., & Farrar, R. (1984). The effects of exercise training on [3H]-spiperone binding in rat striatum. Pharmacology Biochemistry and Behavior, 20(6), 863-867. http://dx.doi.org/10.1016/0091-3057(84)90008-x 
Hagiwara, A., Cornu, M., Cybulski, N., Polak, P., Betz, C., Trapani, F., ... & Hall, M.N. (2012). Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell metabolism, 15(5), 725-738. http://dx.doi.org/10.1016/j.cmet.2012.03.015 
Hazlehurst, J.M., Woods, C., Marjot, T., Cobbold, J.F., & Tomlinson, J.W. (2016). Non-alcoholic fatty liver disease and diabetes. Metabolism, 65(8), 1096–1108. http://dx.doi.org/10.1016/j.metabol.2016.01.001 
Horton, J.D., Goldstein, J.L., & Brown, M.S. (2002). SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. The Journal of Clinical Investigation, 109(9), 1125-1131.  http://dx.doi.org/10.1172/jci15593
Iizuka, K., Bruick, R.K., Liang, G., Horton, J.D., & Uyeda, K. (2004). Deficiency of carbohydrate response element-binding protein (ChrebP) reduces lipogenesis as well as glycolysis. Proceedings of the National Academy of Sciences, 101, 7281-7286. http://dx.doi.org/10.1073/pnas.0401516101 
Isaza, S.C., del Pozo-Maroto, E., Domínguez-Alcón, L., Elbouayadi, L., González-Rodríguez, Á., & García-Monzón, C. (2020). Hypoxia and non-alcoholic fatty liver diseas. Frontiers in Medicine, 7, 578001. http://dx.doi.org/10.3389/fmed.2020.578001 
Ito, M., Suzuki, J., Tsujioka, S., Sasaki, M., Gomori, A., Shirakura, T., ... Iwaasa, H. (2007). Longitudinal analysis of murine steatohepatitis model induced by chronic exposure to high‐fat diet. Hepatology Research, 37(1), 50-57. http://dx.doi.org/10.1111/j.1872-034x.2007.00008.x 
Jendzjowsky, N.G., & DeLorey, D.S. (2011). A prospective evaluation of non-interval-and interval-based exercise training progressions in rodents. Applied Physiology, Nutrition, and Metabolism, 36(5), 723-729. http://dx.doi.org/10.1139/h11-092 
Hazlehurst, J.M., Woods, C., Marjot, T., Cobbold, J. F., & Tomlinson, J.W. (2016). Non-alcoholic fatty liver disease and diabetes. Metabolism: Clinical and Experimental, 65(8), 1096–1108. http://dx.doi.org/10.1016/j.metabol.2016.01.001 
Kato, M., Higuchi, N., & Enjoji, M. (2008). Reduced hepatic expression of adipose tissue triglyceride lipase and CGI-58 may contribute to the development of non-alcoholic fatty liver disease in patients with insulin resistance. Scandinavian Journal of Gastroenterology, 43(8), 1018-1019. http://dx.doi.org/10.1080/00365520802008140 
Kawaguchi, T., Takenoshita, M., Kabashima, T., & Uyeda, K. (2001). Glucose and cAMP regulate the L-type pyruvate kinase gene by phosphorylation/dephosphorylation of the carbohydrate response element binding protein. Proceedings of the National Academy of Sciences, 98(24), 13710-13715. http://dx.doi.org/10.1073/pnas.231370798 
Keating, S.E., George, J., & Johnson, N.A. (2015). The benefits of exercise for patients with non-alcoholic fatty liver disease. Expert Review of Gastroenterology & Hepatology, 9(10), 1247-1250. http://dx.doi.org/10.1586/17474124.2015.1075392 
Kennedy, S.L., Stanley, W.C., Panchal, A.R., & Mazzeo, R.S. (2001). Alterations in enzymes involved in fat metabolism after acute and chronic altitude exposure. Journal of Applied Physiology, 90(1), 17-22. http://dx.doi.org/10.1152/jappl.2001.90.1.17 
Khamzina, L., & Veilleux, A.S. Bergeron, B. & Marette., A. (2005). Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: Possible involvement in obesity-linked insulin resistance. Endocrinology, 146, 1473-1481. http://dx.doi.org/10.1210/en.2004-0921 
Kim, M., Yoon, E.L., Cho, S., Lee, C.M., Kang, B.K., Park, H., ... & Nah, E.H. (2022). Prevalence of advanced hepatic fibrosis and comorbidity in metabolic dysfunction‐associated fatty liver disease in Korea. Liver International, 42(7), 1536-1544. http://dx.doi.org/10.1111/liv.15259 
Kim, M.-W., Bang, M.-S., Han, T.-R., Ko, Y.-J., Yoon, B.-W., Kim, J.-H., ... & Kim, M.-H. (2005). Exercise increased BDNF and trkB in the contralateral hemisphere of the ischemic rat brain. Brain Research, 1052(1), 16-21. http://dx.doi.org/10.1016/j.brainres.2005.05.070 
la Fuente, F.P., Quezada, L., Sepúlveda, C., Monsalves-Alvarez, M., Rodríguez, J. M., Sacristán, C., ... & Troncoso, R. (2019). Exercise regulates lipid droplet dynamics in normal and fatty liver. Molecular and Cell Biology of Lipids, 1864(12), 158519. http://dx.doi.org/10.1016/j.bbalip.2019.158519 
Li, H., Dun, Y., Zhang, W., You, B., Liu, Y., Fu, S., ... & Liu, S. (2021a). Exercise improves lipid droplet metabolism disorder through activation of AMPK-mediated lipophagy in NAFLD. Life Sciences, 273, 119314. http://dx.doi.org/10.1016/j.lfs.2021.119314 
Li, T., Guo, W., & Zhou, Z. (2021b). Adipose Triglyceride Lipase in Hepatic Physiology and Pathophysiology. Biomolecules, 12(1),  57.  http://dx.doi.org/10.3390/biom12010057 
Li, S., Brown, M.S., & Goldstein, J.L. (2010). Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proceedings of the National Academy of Sciences, 107(8), 3441-3446. http://dx.doi.org/10.1073/pnas.0914798107 
Li, S., Ogawa, W., Emi, A., Hayashi, K., Senga, Y., Nomura, K., ... & Kasuga, M. (2011). Role of S6K1 in regulation of SREBP1c expression in the liver. Biochem Biochemical and Biophysical Research Communications, 412(2), 197-202. http://dx.doi.org/10.1016/j.bbrc.2011.07.038 
Liao, B., & Xu, Y. (2011). Exercise improves skeletal muscle insulin resistance without reduced basal mTOR/S6K1 signaling in rats fed a high-fat diet. European Journal of Applied Physiology. 111(11), 2743-2752. http://dx.doi.org/10.1007/s00421-011-1892-5 
Livak, K.J., & Schmittgen, T.D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 25(4), 402-408. http://dx.doi.org/10.1006/meth.2001.1262 
Luo, Y., Chen, Q., Zou, J., Fan, J., Li, Y., & Luo, Z. (2022). Chronic intermittent hypoxia exposure alternative to exercise alleviates high-fat-diet-induced obesity and fatty liver. International Journal of Molecular Sciences, 23(9), 5209. http://dx.doi.org/10.3390/ijms23095209 
Mahat, B., Mauger, J F., & Imbeault, P. (2021). Effects of different oxygen tensions on differentiated human preadipocytes lipid storage and mobilisation. Archives of  Physiology & Biochemistry, 127(1), 37-43. http://dx.doi.org/10.1080/13813455.2019.1609995 
Maiti, P., Muthuraju, S., Ilavazhagan, G., & Singh, S.B. (2008). Hypobaric hypoxia induces dendritic plasticity in cortical and hippocampal pyramidal neurons in rat brain. Behavioural Brain Research, 189(2), 233-243. http://dx.doi.org/10.1016/j.bbr.2008.01.007 
Melo, L., Bilici, M., Hagar, A., & Klaunig, J.E. (2021). The effect of endurance training on non-alcoholic fatty liver disease in mice. Physiological Reports, 9(15), e14926. http://dx.doi.org/10.14814/phy2.14926 
Mylonis, I., Simos, G., & Paraskeva, E. (2019). Hypoxia-inducible factors and the regulation of lipid metabolism. Cells, 8(3), 214.  http://dx.doi.org/10.3390/cells8030214 
Ong, K.T., Mashek, M.T., Bu, S.Y., Greenberg, A.S., & Mashek, D.G. (2011). Adipose triglyceride lipase is a major hepatic lipase that regulates triacylglycerol turnover and fatty acid signaling and partitioning. Hepatology, 53(1), 116-126. http://dx.doi.org/10.1002/hep.24006 
O’Rourke, R.W., Meyer, K.A., Gaston, G., White, A.E., Lumeng, C.N., & Marks, D.L. (2013). Hexosamine biosynthesis is a possible mechanism underlying hypoxia’s effects on lipid metabolism in human adipocytes. Public Library of Science, 8(8), e71165. http://dx.doi.org/10.1371/journal.pone.0071165 
Ou, L., & Leiter, J. (2004). Effects of exposure to a simulated altitude of 5500 m on energy metabolic pathways in rats. Respiratory Physiology & Neurobiology, 141(1), 59-71. http://dx.doi.org/10.1016/j.resp.2004.04.001 
Peterson, T.R., Sengupta, S.S., Harris, T.E., Carmack, A.E., Kang, S.A., Balderas, E., ... & Sabatini, D.M. (2011). mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell, 146(3), 408-420. http://dx.doi.org/10.1016/j.cell.2011.06.034 
Qiu, S., Xu, H., Lin, Z., Liu, F., & Tan, F. (2019). The blockade of lipophagy pathway is necessary for docosahexaenoic acid to regulate lipid droplet turnover in hepatic stellate cells. Biomedicine & Pharmacotherapy, 109, 1841-1850. http://dx.doi.org/10.1016/j.biopha.2018.11.035 
Rezadoost, M.H., Kordrostami, M., & Kumleh, H.H. (2016). An efficient protocol for isolation of inhibitor-free nucleic acids even from recalcitrant plants. Biotech, 6(1), 61. http://dx.doi.org/10.1007/s13205-016-0375-0 
Ricoult, S.J., & Manning, B.D. (2013). The multifaceted role of mTORC1 in the control of lipid metabolism. EMBO Reports, 14(3), 242-251.  http://dx.doi.org/10.1038/embor.2013.5 
Sabatini, D.M. (2017). Twenty-five years of mTOR: Uncovering the link from nutrients to growth. Proceedings of the National Academy of Sciences, 114(45), 11818-11825. http://dx.doi.org/10.1073/pnas.1716173114 
SaiRam, M., Sharma, S., Dipti, P., Pauline, T., Kain, A., Mongia, S., ... & Devendra, K. (1998). Effect of hypobaric hypoxia on immune function in albino rats. International Journal of Biometeorology, 42, 55-59. http://dx.doi.org/10.1007/s004840050084 
Santos-Alves, E., Marques-Aleixo, I., Rizo-Roca, D., Torrella, J., Oliveira, P., Magalhães, J., & Ascensão, A. (2015). Exercise modulates liver cellular and mitochondrial proteins related to quality control signaling. Life Sciences, 135, 124-130. http://dx.doi.org/10.1016/j.lfs.2015.06.007 
Schweiger, M., Lass, A., Zimmermann, R., Eichmann, T. O., & Zechner, R. (2009). Neutral lipid storage disease: genetic disorders caused by mutations in adipose triglyceride lipase/PNPLA2 or CGI-58/ABHD5. American Journal of Physiology-Endocrinology and Metabolism. 297(2), E289–E296. http://dx.doi.org/10.1152/ajpendo.00099.2009 
Shimano, H., & Sato, R. (2017). SREBP-regulated lipid metabolism: convergent physiology—divergent pathophysiology. Nature Reviews Endocrinology, 13(12), 710-730.  http://dx.doi.org/10.1038/nrendo.2017.91 
Simon, T.G., Roelstraete, B., Hartjes, K., Shah, U., Khalili, H., Arnell, H., & Ludvigsson, J.F. (2021). Non-alcoholic fatty liver disease in children and young adults is associated with increased long-term mortality. Journal of Hepatology, 75(5), 1034-1041.  http://dx.doi.org/10.1016/j.jhep.2021.06.034 
Suk, M., & Shin, Y. (2015). Effect of high-intensity exercise and high-fat diet on lipid metabolism in the liver of rats. Journal of Exercise Nutrition & Biochemistry, 19(4), 289. http://dx.doi.org/10.5717/jenb.2015.15122303 
Sullivan, S. (2010). Implications of diet on nonalcoholic fatty liver disease. Current Opinion in Gastroenterology, 26(2), 160.  http://dx.doi.org/10.1097/mog.0b013e3283358a58 
Takahashi, Y., Soejima, Y., & Fukusato, T. (2012). Animal models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World Journal of Gastroenterology: WJG, 18(19), 2300. http://dx.doi.org/10.3748/wjg.v18.i19.2300 
Tsuru, H., Osaka, M., Hiraoka, Y., & Yoshida, M. (2020). HFD-induced hepatic lipid accumulation and inflammation are decreased in Factor D deficient mouse. Scientific Reports, 10(1), 17593.  http://dx.doi.org/10.1038/s41598-020-74617-5 
Tu, G., Dai, C., Qu, H., Wang, Y., & Liao, B. (2020). Role of exercise and rapamycin on the expression of energy metabolism genes in liver tissues of rats fed a high‑fat diet. Molecular Medicine Reports, 22(4), 2932-2940.  http://dx.doi.org/10.3892/mmr.2020.11362 
Wang, R., Guo, S., Tian, H., Huang, Y., Yang, Q., Zhao, K., . . . & Liu, T. (2019). Hypoxic training in obese mice improves metabolic disorder. Front Endocrinol (Lausanne), 10, 527.  http://dx.doi.org/10.3389/fendo.2019.00527 
Wang, Y., Shi, M., Fu, H., Xu, H., Wei, J., Wang, T., & Wang, X. (2010). Mammalian target of the rapamycin pathway is involved in non-alcoholic fatty liver disease. Molecular Medicine Reports, 3(6), 909-915. http://dx.doi.org/10.3892/mmr.2010.365 
Wu, B., Xu, C., Tian, Y., Zeng, Y., Yan, F., Chen, A., . . . & Chen, L. (2022). Aerobic exercise promotes the expression of Atgl and attenuates inflammation to improve hepatic steatosis via lncRNA SRA. Scientific Reports, 12(1), 5370.  http://dx.doi.org/10.21203/rs.3.rs-1035461/v1 
Wu, F.F., Zhang, K.L., Wang, Z.M., Yang, Y., Li, S.H., Wang, J.Q., ... Wang, Y.Y. (2021). Benefit of a single simulated hypobaric hypoxia in healthy mice performance and analysis of mitochondria-related gene changes. Scientific Reports, 11(1), 4494.  http://dx.doi.org/10.1038/s41598-020-80425-8 
Wu, J.W., Wang, S.P., Alvarez, F., Casavant, S., Gauthier, N., Abed, L., ... & Mitchell, G.A. (2011). Deficiency of liver adipose triglyceride lipase in mice causes progressive hepatic steatosis. Hepatology, 54(1), 122-132.  http://dx.doi.org/10.1002/hep.24338 
Yan, Y.H., Chou, C.C., Lee, C.T., Liu, J.Y., & Cheng, T.J. (2011). Enhanced insulin resistance in diet-induced obese rats exposed to fine particles by instillation. Inhalation Toxicology, 23(9), 507-519.  http://dx.doi.org/10.3109/08958378.2011.587472 
Yang, Q., Sun, S., Liu, W., Liu, Q., & Wang, J. (2020). Hypoxia training improves hepatic steatosis partly by downregulation of CB1 receptor in obese mice. Biochemical and Biophysical Research Communications, 525(3), 639-645. http://dx.doi.org/10.1016/j.bbrc.2020.02.134 
Yasari, S., Prud’homme, D., Wang, D., Jankowski, M., Levy, E., Gutkowska, J., & Lavoie, J.M. (2010). Exercise training decreases hepatic SCD-1 gene expression and protein content in rats. Molecular and Cellular Biochemistry, 335(1-2), 291-299.  http://dx.doi.org/10.1007/s11010-009-0279-y 
Yecies, J.L., Zhang, H.H., Menon, S., Liu, S., Yecies, D., Lipovsky, A.I., ... & Manning, B.D. (2011). Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metabolism, 14(1), 21-32.  http://dx.doi.org/10.1016/j.cmet.2011.06.002 
Younossi, Z.M., Corey, K.E., Alkhouri, N., Noureddin, M., Jacobson, I., Lam, B., ... & Ravendhra, N. (2020). Clinical assessment for high‐risk patients with non‐alcoholic fatty liver disease in primary care and diabetology practices. Alimentary Pharmacology & Therapeutics, 52(3), 513-526. http://dx.doi.org/10.1111/apt.15830 
Yousefi, S., & Simon, H.-U. (2009). Autophagy in cancer and chemotherapy. Death Receptors and Cognate Ligands in Cancer, 183–190. http://dx.doi.org/10.1007/400_2008_25