The Effect of Aerobic Exercise and Resveratrol on Endoplasmic Reticulum Stress in Heart Tissue of NAFLD Rats with HFD
Subject Areas : Exercise Physiology and Performance
Samira Rezvani Nteghi
1
,
Ahmad Abdi
2
*
1 - Department of Physical Education and Sport Science, Am.C., Islamic Azad University, Amol, Iran
2 - Department of Physical Education and Sport Science, Am.C., Islamic Azad University, Amol, Iran
Keywords: Exercise, Resveratrol, GRP78, CHOP, Non-Alcoholic Fatty Liver Disease, endoplasmic reticulum stress,
Abstract :
Background: Non-alcoholic fatty liver disease (NAFLD) is closely linked to extrahepatic complications, including cardiac dysfunction. Endoplasmic reticulum stress (ERS) is implicated in NAFLD progression, but its role in associated cardiac pathology remains understudied. This study evaluated the combined effects of aerobic exercise and resveratrol (RSV) on cardiac ERS markers (GRP78, CHOP) in NAFLD rats induced by a high-fat diet (HFD).
Methods: Forty male Wistar rats (159.95 ± 19.70 g) were divided into five groups: healthy control (CON), NAFLD model (HFD), HFD + exercise (EX), HFD + RSV, and HFD + EX + RSV. RSV (20 mg/kg/day) was administered orally, while aerobic exercise involved treadmill running (15–20 m/min, 5 days/week) for 8 weeks.
Results: HFD-induced NAFLD significantly increased GRP78 and CHOP expression vs. CON (p < 0.001). Both EX (GRP78: p = 0.014; CHOP: p = 0.046) and RSV (GRP78: p = 0.015; CHOP: p = 0.042) reduced these markers compared to HFD. The EX + RSV combination showed greater efficacy, lowering GRP78 and CHOP vs. HFD (p < 0.001), EX (GRP78: p = 0.039; CHOP: p = 0.038), and RSV (GRP78: p = 0.038; CHOP: p = 0.041).
Conclusion: Aerobic exercise and RSV independently ameliorate cardiac ERS in NAFLD, but their synergistic effect yields superior outcomes. This highlights the potential of lifestyle-pharmacological interventions for NAFLD-related cardiac complications.
1. Lazo M, Hernaez R, Eberhardt MS, Bonekamp S, Kamel I, Guallar E, et al. Prevalence of nonalcoholic fatty liver disease in the United States: The Third National Health and Nutrition Examination Survey, 1988–1994. Am J Epidemiol. 2013;178(1):38-45. doi: 10.1093/aje/kws448
2. Schwenger KJ, Fischer SE, Jackson TD, Okrainec A, Allard JP. Non-alcoholic fatty liver disease in morbidly obese individuals undergoing bariatric surgery: prevalence and effect of the pre-bariatric very low-calorie diet. Obes Surg. 2018;28(4):1109-16. doi: 10.1007/s11695-017-2980-3
3. Younossi ZM. Non-alcoholic fatty liver disease–a global public health perspective. J Hepatol. 2019;70(3):531-44. doi: 10.1016/j.jhep.2018.10.033.
4. Kaneko M, Imaizumi K, Saito A, Kanemoto S, Asada R, Matsuhisa K, et al. ER stress and disease: toward prevention and treatment. Biol Pharm Bull. 2017;40(9):1337-43. doi: 10.1248/bpb.b17-00342
5. Lebeaupin C, Vallée D, Hazari Y, Hetz C, Chevet E, Bailly-Maitre B. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J Hepatol. 2018;69(4):927-47. doi: 10.1016/j.jhep.2018.06.008
6. Cybulsky AV. Endoplasmic reticulum stress, the unfolded protein response and autophagy in kidney diseases. Nat Rev Nephrol. 2017;13(11):681-96. doi: 10.1038/nrneph.2017.121
7. Marques CMM, Motta VF, Torres TS, Aguila MB, Mandarim-de-Lacerda CA. Beneficial effects of exercise training (treadmill) on insulin resistance and nonalcoholic fatty liver disease in high-fat fed C57BL/6 mice. Braz J Med Biol Res. 2010;43(5):467-75. doi: 10.1590/S0100-879X2010005000021
8. Oakes SA, Papa FR. The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol. 2015;10:173-94. doi:10.1146/annurev-pathol-012513-104649
9. Deldicque L, Cani PD, Delzenne NM, Baar K, Francaux M. Endurance training in mice increases the unfolded protein response induced by a high-fat diet. J Physiol Biochem. 2013;69(2):215-25. doi:10.1007/s13105-012-0201-6
10. Kristensen CM, Brandt CT, Ringholm S, Pilegaard H. PGC-1α in aging and lifelong exercise training-mediated regulation of UPR in mouse liver. Exp Gerontol. 2017;98:124-33. doi: 10.1016/j.exger.2017.08.007
11. Meng X, Zhou J, Zhao C-N, Gan R-Y, Li H-B. Health benefits and molecular mechanisms of resveratrol: A narrative review. Foods. 2020;9(3):340. doi:10.3390/foods9030340
12. Singh AK, Vinayak M. Resveratrol alleviates inflammatory hyperalgesia by modulation of reactive oxygen species (ROS), antioxidant enzymes and ERK activation. Inflamm Res. 2017;66(10):911-21. doi:10.1007/s00011-017-1066-4
13. Springer M, Moco S. Resveratrol and its human metabolites—Effects on metabolic health and obesity. Nutrients. 2019;11(1):143. doi:10.3390/nu11010143
14. Yuan D, Liu X, Fang Z, Du L, Chang J, Lin S. Protective effect of resveratrol on kidney in rats with diabetic nephropathy and its effect on endoplasmic reticulum stress. Eur Rev Med Pharmacol Sci. 2018;22(5):1485-93. doi:10.26355/eurrev\_201803\_14509
15. Petrovski G, Gurusamy N, Das DK. Resveratrol in cardiovascular health and disease. Ann N Y Acad Sci. 2011;1215(1):22-33. doi:10.1111/j.1749-6632.2010. 05843.x
16. Xie YK, Zhou X, Yuan HT, Qiu J, Xin DQ, Chu XL, et al. Resveratrol reduces brain injury after subarachnoid hemorrhage by inhibiting oxidative stress and endoplasmic reticulum stress. Neural Regen Res. 2019;14(10):1734–42. doi:10.4103/1673-5374.257529
17. Badiola N, Penas C, Miñano-Molina A, Barneda-Zahonero B, Fadó R, Sánchez-Opazo G, et al. Induction of ER stress in response to oxygen-glucose deprivation of cortical cultures involves the activation of the PERK and IRE-1 pathways and of caspase-12. Cell Death Dis. 2011;2(4): e149. doi:10.1038/cddis.2011.31
18. Hammadi M, Oulidi A, Gackière F, Katsogiannou M, Slomianny C, Roudbaraki M, et al. Modulation of ER stress and apoptosis by endoplasmic reticulum calcium leak via translocon during unfolded protein response: involvement of GRP78. FASEB J. 2013;27(4):1600–9. doi:10.1096/fj.12-218875
19. Huang TT, Lai HC, Chen YB, Chen LG, Wu YH, Ko YF, et al. cis-Resveratrol produces anti-inflammatory effects by inhibiting canonical and non-canonical inflammasomes in macrophages. Innate Immun. 2014;20(7):735–50. doi:10.1177/1753425913507096
20. Efati M, Khorrami M, Zarei Mahmmodabadi A, Raouf Sarshoori J. Induction of an Animal Model of Non-Alcoholic Fatty Liver Disease Using a Formulated High-Fat Diet. J Babol Univ Med Sci. 2016;18(11):57–62. doi: 10.22088/jbums.18.11.57
21. Linden MA, Fletcher JA, Morris EM, Meers GM, Laughlin MH, Booth FW, et al. Treating NAFLD in OLETF rats with vigorous-intensity interval exercise training. Med Sci Sports Exerc. 2015;47(3):556–67. doi:10.1249/MSS.0000000000000430
22. Monserrat Hernández-Hernández E, Serrano-García C, Antonio Vázquez-Roque R, Díaz A, Monroy E, Rodríguez-Moreno A, et al. Chronic administration of resveratrol prevents morphological changes in prefrontal cortex and hippocampus of aged rats. Synapse. 2016;70(5):206–17. doi:10.1002/syn.21888
23. Lei ZX, Wang JJ, Li K, Liu P. Herp knockout protects against nonalcoholic fatty liver disease in mice on a high fat diet. Kaohsiung J Med Sci. 2021;37(6):487–96. doi:10.1002/kjm2.12349
24. Mansour SZ, Moustafa EM, Moawed FS. Modulation of endoplasmic reticulum stress via sulforaphane-mediated AMPK upregulation against nonalcoholic fatty liver disease in rats. Cell Stress Chaperones. 2022;27(5):499–511. doi:10.1007/s12192-022-01286-w
25. Sathyanarayana AR, Lu CK, Liaw CC, Chang CC, Han HY, Green BD, et al. 1,2,3,4,6-Penta-O-galloyl-d-glucose interrupts the early adipocyte lifecycle and attenuates adiposity and hepatic steatosis in mice with diet-induced obesity. Int J Mol Sci. 2022;23(7):4052. doi:10.3390/ijms23074052
26. Gonzalez-Rodriguez A, Mayoral R, Agra N, Valdecantos M, Pardo V, Miquilena-Colina M, et al. Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis. 2014;5(4): e1179. doi:10.1038/cddis.2014.179
27. Li J, Huang L, Xiong W, Gu C, Zhang S, Xue X. Effect of aerobic exercise on GRP78 and ATF6 expressions in mice with non-alcoholic fatty liver disease. Sports Med Health Sci. 2022. doi: 10.1016/j.smhs.2022.03.003
28. Tan N, Li X, Zhai L, Liu D, Li J, Yokota H, et al. Effects of knee loading on obesity‐related non‐alcoholic fatty liver disease in an ovariectomized mouse model with high‐fat diet. Hepatol Res. 2018;48(10):839–49. doi: 10.1111/hepr.13068
29. Li J, Huang L, Xiong W, Qian Y, Song M. Aerobic exercise improves non-alcoholic fatty liver disease by down-regulating the protein expression of the CNPY2-PERK pathway. Biochem Biophys Res Commun. 2022;603:35–40. doi: 10.1016/j.bbrc.2022.02.084
30. Paes L, Lima D, Matsuura C, de Souza MdG, Cyrino F, Barbosa C, et al. Effects of moderate and high intensity isocaloric aerobic training upon microvascular reactivity and myocardial oxidative stress in rats. PLoS One. 2020;15(2):e0218228. doi: 10.1371/journal.pone.0218228
31. Estébanez B, De Paz JA, Cuevas MJ, González-Gallego J. Endoplasmic reticulum unfolded protein response, aging and exercise: An update. Front Physiol. 2018; 9:1744. doi:10.3389/fphys.2018.01744
32. Li H, Min Q, Ouyang C, Lee J, He C, Zou M-H, et al. AMPK activation prevents excess nutrient-induced hepatic lipid accumulation by inhibiting mTORC1 signaling and endoplasmic reticulum stress response. Biochim Biophys Acta Mol Basis Dis. 2014;1842(9):1844–54. doi: 10.1016/j.bbadis.2014.06.004
33. Ding S, Jiang J, Zhang G, Bu Y, Zhang G, Zhao X. Resveratrol and caloric restriction prevent hepatic steatosis by regulating SIRT1-autophagy pathway and alleviating endoplasmic reticulum stress in high-fat diet-fed rats. PLoS One. 2017;12(8):e0183541. doi: 10.1371/journal.pone.0183541
34. Pan Q-R, Ren Y-L, Liu W-X, Hu Y-J, Zheng J-S, Xu Y, et al. Resveratrol prevents hepatic steatosis and endoplasmic reticulum stress and regulates the expression of genes involved in lipid metabolism, insulin resistance, and inflammation in rats. Nutr Res. 2015;35(7):576–84. doi: 10.1016/j.nutres.2015.04.003
35. Rui Y, Cheng J, Qin L, Shan C, Chang J, Wang G, et al. Effects of vitamin D and resveratrol on metabolic associated markers in liver and adipose tissue from SAMP8 mice. Exp Gerontol. 2017;93:16–28. doi: 10.1016/j.exger.2017.04.003
36. Yan W-J, Liu R-B, Wang L-K, Ma Y-B, Ding S-L, Deng F, et al. Sirt3-mediated autophagy contributes to resveratrol-induced protection against ER stress in HT22 cells. Front Neurosci. 2018;12:116. doi: 10.3389/fnins.2018.00116
37. Ardid-Ruiz A, Ibars M, Mena P, Del Rio D, Muguerza B, Bladé C, et al. Potential involvement of peripheral leptin/STAT3 signaling in the effects of resveratrol and its metabolites on reducing body fat accumulation. Nutrients. 2018;10(11):1757. doi: 10.3390/nu10111757
38. Bal NB, Bostancı A, Sadi G, Dönmez MO, Uludağ MO, Demirel-Yilmaz E. Resveratrol and regular exercise may attenuate hypertension-induced cardiac dysfunction through modulation of cellular stress responses. *Life Sci.* 2022;120424. doi: 10.1016/j.lfs.2022.120424
39. Zhang Y, Weng Y, Wang D, Wang R, Wang L, Zhou J, et al. Curcumin in combination with aerobic exercise improves follicular dysfunction via inhibition of the hyperandrogen-induced IRE1α/XBP1 endoplasmic reticulum stress pathway in PCOS-like rats. Oxid Med Cell Longev. 2021;2021:1–22. doi: 10.1155/2021/6694150