اثر تمرینات استقامتی بر پیام رسانی سنتز اسیدهای صفراوی در موش های مبتلا به کبد چرب غیرالکلی

محورهای موضوعی : فصلنامه زیست شناسی جانوری

مهری قلی پور ¹ , نجمه رضائیان ^{2 *} , محمد کریمی ³ , صادق چراغ بیرجندی ⁴

1 - گروه فیزیولوژی ورزشی، واحد بجنورد، دانشگاه آزاد اسلامی، بجنورد، ایران
2 - گروه فیزیولوژی ورزشی، واحد بجنورد، دانشگاه آزاد اسلامی، بجنورد، ایران
3 - گروه فیزیولوژی ورزش، دانشگاه صنعتی قم، قم، ایران
4 - گروه فیزیولوژی ورزشی، واحد بجنورد، دانشگاه آزاد اسلامی، بجنورد، ایران

تاریخ دریافت : 1401/10/25 تاریخ پذیرش : 1401/12/05 تاریخ انتشار : 1402/03/01

کلید واژه: کبد چرب غیرالکلی, اسیدهای صفراوی, پیام رسانی, فعالیت ورزشی استقامتی,

چکیده مقاله :

بیماری کبد چرب غیرالکلی (NAFLD) شایع ترین اختلال عملکرد کبدی و یکی از علل مهم بروز مرگ و میر ناشی از بیماری های مزمن کبدی است. هدف از مطالعه حاضر بررسی اثر هشت هفته تمرینات استقامتی بر اسیدهای صفراوی (BA) کبدی، بیان نسبی گیرنده ایکس فارنزوئید (FXR)، عامل رشد فیبروبلاست 15 (FGF15)، گیرنده 4 عامل رشد فیبروبلاست (FGFR4) و پروتئین بتا کلوتو (KLB) در موش‌های مبتلا به کبد چرب غیرالکلی بود. در این مطالعه تجربی تعداد 16 سر موش صحرایی نر نژاد ویستار با وزن تقریبی 120-160 گرم، پس از القای شرایط NAFLD، با شش هفته رژیم غذایی پرچرب به طور تصادفی در دو گروه مساوی (8 سر در هر گروه) شامل گروه‌های؛ کنترل (C) و تمرین استقامتی (E) تقسیم شدند. گروه تمرین E در یک پروتکل تمرین فزاینده دویدن روی تردمیل با شدت 65 درصد حداکثر اکسیژن مصرفی و تواتر 5 روز متوالی در هفته شرکت کردند. 48 ساعت پس از آخرین جلسه تمرین، آزمودنی‌ها کشته شده و نمونه گیری بافت کبد و نمونه خون برای ارزیابی متغیرهای تحقیق انجام گردید. تجزیه و تحلیل داده ها با استفاده از آزمون t مستقل انجام شد. یافته ها نشان داد پروتکل تمرین E در مقایسه با گروه کنترل، منجر به کاهش معنادار در مقادیر کبدی BA شد (0001/0= p). همچنین افزایش معنادار در بیان نسبی FXR، FGF15، FGFR4 و مقادیر پروتئین KLB مشاهده شد (0001/0 = p). در مجموع به نظر می رسد فعالیت ورزشی استقامتی می توانند اثرات مثبتی بر متغیرهای درگیر در پیام رسانی سنتز اسیدهای صفراوی کبدی داشته باشد.

چکیده انگلیسی:

Non-alcoholic fatty liver disease (NAFLD) is the most common liver dysfunction and one of the most important causes of death from chronic liver diseases. The purpose of this study is to investigate the effect of eight weeks of endurance training compared to resistance training on liver bile acids (BA), relative expression of farnesoid X receptor (FXR), fibroblast growth factor 15 (FGF15), fibroblast growth factor receptor 4 (FGFR4) and beta protein Klotho (KLB) in rats with non-alcoholic fatty liver disease. In this experimental study, 16 Wistar rats with an approximate weight of 120-160 grams, after induction of NAFLD conditions, with six weeks of high-fat diet were randomly divided into two equal groups (8 rats in each group), including; Control (C), endurance training (E). group E participated in an incremental treadmill exercise protocol with an intensity of 65% of maximal oxygen consumption and a frequency of 5 sessions per week. 48 hours after the last training session, the subjects were sacrificed and liver tissue and blood samples were taken to evaluate the research variables. Data were analyzed by using independent t-test. The findings showed that E training protocols led to a significant decrease in liver BA values (p = 0.0001). Also, in the E training group, a significant increase in the relative expression of FXR, FGF15, FGFR4 and KLB protein levels  was observed (p = 0.0001). In conclusion, it seems that endurance exercise can have positive effects on the variables involved in the signaling of bile acid synthesis. .

منابع و مأخذ:

1. Afkhamy Ardakani M. 2020. The effect of Aerobic training on Klotho-FGF23 axis and arterial calcification in type 2 diabetic Postmenopausal women. Journal of Sport and Exercercise Psychology, 13(1):27-38. (In Persion).


2. Agrawal A., Parlee S., Perez-Tilve D., Li P., Pan J., Mroz, P.A., Kruse Hansen A.M., Andersen B., Finan B., Kharitonenkov A., DiMarchi R.D. 2018. Molecular elements in FGF19 and FGF21 defining KLB/FGFR activity and specificity. Molecular Metabolism, 13:45-55.


3. Barikani A., Pashaeypoor S. 2019. Lifestyle in Non-alcoholic Fatty Liver: A Review. Iranian Journal of Nursing Research, 13(6) :39-47.


4. Berezin A.E., Berezin A.A. 2019. Impaired function of fibroblast growth factor 23/Klotho protein axis in prediabetes and diabetes mellitus: Promising predictor of cardiovascular risk. Diabetes and Metabolic Syndrome; 13(4):2549-2556.


5. Bolboli L., Khajehlandi M. 2021. The Effect of Six Weeks of Moderate-Intensity Endurance Training on Serum Levels of Klotho and Expression of the Fibroblast-23 Growth Factor Gene (FGF23) in the Hearts of Diabetic Rats: An Experimental Study. Journal of Rafsanjan University of Medical Sciences; 20(4):371-386


6. Carbajo-Pescador S., Porras D., García-Mediavilla M.V. 2019. “Beneficial effects of exercise on gut microbiota functionality and barrier integrity, and gut-liver axis crosstalk in anin vivomodel of early obesity and NAFLD. Disease Models and Mechanisms, 12(5):dmm039206.


7. Chávez-Talavera O., Tailleux A., Lefebvre P., Staels B. 2017. Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease. Gastroenterology, 152(7):1679-1694.


8. Chen J., Vitetta L. 2020. “Gut microbiota metabolites in NAFLD pathogenesis and therapeutic implications,” International Journal of Molecular Sciences, 21(15):5214.


9. Côté I., Sock E.T.N., Lévy É., Lavoie J.M. 2013. An atherogenic diet decreases liver FXR gene expression and causes severe hepatic steatosis and hepatic cholesterol accumulation: effect of endurance training.European Journal of Nutrition,52(5):1523-1532.


10. Doi S., Zou Y., Togao O., Pastor J.V., John G.B., Wang L. 2011. Klotho Inhibits Transforming Growth Factor-Β1 (TGF-Β1) Signaling and Suppresses Renal Fibrosis and Cancer Metastasis in Mice. Journal of Biological Chemistry, 286(10):8655-8665.


11. Duan Y., Zhang F., Yuan W. 2019. Hepatic cholesterol accumulation ascribed to the activation of ileum Fxr-Fgf15 pathway inhibiting hepatic Cyp7a1 in high-fat diet-induced obesity rats. Life Sciences, 232:116638.


12. Fabbrini E., Sullivan S., Klein S. 2010. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology, 51(2):679-89.


13. Fan M., Wang X., Xu G., Yan Q., Huang W. 2015. Bile acid signaling and liver regeneration. Biochimca et Biophysica Acta., 1849(2):196-200.


14. Farahnak Z., Tomaz L.M., Bergeron R., Chapados N., Lavoie J.M. 2017. The effect of exercise training on upregulation of molecular markers of bile acid metabolism in the liver of ovariectomized rats fed a cholesterol-rich diet.ARYA Atherosclerosis,13(4):184.


15. Fiorucci S., Cipriani S., Mencarelli A., Baldelli F., Bifulco G., Zampella A. 2011. Farnesoid X receptor agonist for the treatment of liver and metabolic disorders: focus on 6-ethyl-CDCA. Mini Reviews in Medicinal Chemistry, 11:753-762.


16. Fleenor B.S., Marshall K.D., Durrant J.R., Lesniewski L.A., Seals D.R. 2010. Arterial Stiffening with Ageing is Associated with Transforming Growth Factor Β1 Related Changes in Adventitial Collagen: Reversal by Aerobic Exercise. Journal of Physiology, 588(20): 3971-82.


17. Fuchs M. 2012. Non-alcoholic Fatty liver disease: the bile Acid-activated farnesoid x receptor as an emerging treatment target. Journal of Lipids, 2012:934396.


18. Hagio M., Matsumoto M., Yajima T., Hara H., Ishizuka S. 2010. Voluntary wheel running exercise and dietary lactose concomitantly reduce proportion of secondary bile acids in rat feces.Journal of Applied Physiology,109(3):663-668.


19. Hajighasem A., Farzanegi P., Mazaheri Z., Naghizadeh, M., Salehi G. 2018. Effects of resveratrol, exercises and their combination onFarnesoid X receptor, Liver X receptor and Sirtuin 1 gene expression and apoptosis in the liver of elderly rats with nonalcoholic fatty liver.PeerJ, 6:e5522.


20. Hormati A., Shakeri M., Iranikhah A. 2019. Non-alcoholic fatty liver disease. Govaresh; 23:203-212.


21. Inagaki T., Choi M., Moschetta A., Peng L., Cummins C.L., McDonald J.G., Luo, G., Jones S.A., Goodwin B., Richardson J.A., Gerard R.D., Repa J.J., Mangelsdorf D.J. Kliewer SA. 2005. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metabolism, 2:217-225.


22. Jafari M., Rashidlamir A., Dastani M., Fathi M., Alavinya, S.E. 2018. The effect of cardiac rehabilitation on ApoA1 and ApoB in men with coronary heart disease (CHD) after coronary artery bypass graft (CABG). Medical Sciences, 28(2):117-123.


23. Jamali R., Jamali A. 2010. Non-alcoholic fatty liver disease. Journal of Kashan University of Medical Sciences; 14(2):169-181


24. Jiao Y., Lu Y., Li X.Y. 2015. Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis. Acta Pharmacol Sin; 36:44-50.


25. Kaser S., Ebenbichler C., Tilg H. 2010. Pharmacological and non-pharmacological treatment of nonalcoholic fatty liver disease. International Journal of Clinical Practice; 64(7):968-983


26. Kazeminasab F., Marandi S.M., Ghaedi K., Esfarjani F., Nasr-Esfahani M.H. 2019. The effect of endurance training and high-fat diet on PGC-1a/FNDC5/Irisin pathway in male C57BL/6 mice. Sport Physiology, 11(41):63-80. (In Persian)


27. Kliewer S. A., Mangelsdorf D.J. 2015. Bile acids as hormones: the FXR-FGF15/19 Pathway.Dig. Dis.33:327-331.


28. Kontogianni M.D., Tileli N., Margariti A., Georgoulis M., Deutsch M., Tiniakos D., Fragopoulou E., Zafiropoulou R., Manios Y., Papatheodoridis G. 2013. Adherence to the Mediterranean diet is associated with the severity of non-alcoholic fatty liver disease. Clinical Nutrition, 33(4):678-683.


29. Leung C., Rivera L., Furness J.B., Angus P.W. 2016. The role of the gut microbiota in NAFLD.Nature reviews Gastroenterology and Hepatology,13(7):412-425.


30. Luo M., Yan J., Wu L., Wu J., Chen Z., Jiang J., Chen Z., He B. 2021. Probiotics Alleviated Nonalcoholic Fatty Liver Disease in High-Fat Diet-Fed Rats via Gut Microbiota/FXR/FGF15 Signaling Pathway. Journal of Immunology Research, 2021, 2264737.


31. McGettigan B.M., McMahan R.H., Luo Y., Wang X.X., Orlicky D.J., Porsche C., Levi M., Rosen H.R. 2016. Sevelamer improves Steatohepatitis, inhibits liver and intestinal farnesoid X receptor (Fxr), and reverses innate immune dysregulation in a mouse model of non-alcoholic fatty liver disease.Journal of Biological Chemistry; 291:23058–23067.


32. Mirghani S.J., Peeri M., Yaghoobpour Yekani O., Zamani M., Feizolahi F., Nikbin S., Derakhshideh A., Mousavi N., Khojasteh Z., Nasrollahi Z., Khorasani E., Ghodousi Johari E., Afshar T., Azarbayjani M.A. 2019. Role or Synergistic Interaction of Adenosine and Vitamin D3 Alongside High-Intensity Interval Training and Isocaloric Moderate Intensity Training on Metabolic Parameters: Protocol for an Experimental Study. JMIR Research Protocols, 8(1):e10753.


33. Obika M., Noguchi H. 2012. Diagnosis and evaluation of nonalcoholic fatty liver disease. Experimental Diabetes Research, 2012:145754.


34. Piguet A.C., Guarino M., Potaczek D. P., Garn H., Dufour J.F. 2019. Hepatic gene expression in mouse models of non‐alcoholic fatty liver disease after acute exercise.Hepatology Research,49(6):637-652.


35. Qiu Y., Shen L., Fu L., Yang J., Cui C., Li T., Li X., Fu C., Gao X., Wang W., Ning G., Gu Y. 2020. The glucose-lowering effects of α-glucosidase inhibitor require a bile acid signal in mice. Diabetologia, 63(5):1002-1016.


36. Tenhagen M., van Diest P.J., Ivanova I.A., vander Wall, E., vander Groep, P. 2012. Fibroblast growth factor receptors in breast cancer: Expression downstream effects, and possible drug targets. Endocr Relat Cancer, 19(4): R115-129.


37. Teixeira-Lemos E., Nunes S., Teixeira F., Reis F. 2011. Regular physical exercise training assists in preventing type 2 diabetes development: focus on its antioxidant and anti-inflammatory properties. Cardiovascular Diabetology, 10(1):12-15.


38. Thisse B., Thisse C. 2005. Functions and regulations of fibroblast growth factor signaling during embryonic development. Developmental Biology, 287:390-402


39. Thomas C., Bishop D., Moore-Morris T., Mercier J. 2007. Effects of high-intensity training on MCT1, MCT4, and NBC expressions in rat skeletal muscles: influence of chronic metabolic alkalosis. American Journal of Physiology-Endocrinology and Metabolism, 293(4): E916-22.


40. Yaghoobpour Yekani O., Azarbayjani M.A., Peeri M., Farzanegi P. 2018. Effect of type of training on markers of hepatocyte apoptosis in rats fed with high fat diet. Yafte, 19(5):106-116


41. Yao J., Zhou C.S., Ma X., Fu B.Q., Tao L.S., Chen M., Xu Y.P. 2014.FXR agonist GW4064 alleviates endotoxin-induced hepatic inflammation by repressing macrophage activation.World Journal of Gastroenterology, 20:14430-14441.