Objective To explore the effects of curcumin combined with aerobic exercise on hepatic steatosis in rats and the possible mechanisms. Methods Fifty 5 w old male SD rats were randomly divided into control group (regular diet+no special exercise intervention, group C), model group (high-fat diet+no special exercise intervention, group M), curcumin group (high-fat diet+curcumin+no special exercise intervention, group Cu), aerobic exercise group (high-fat diet+aerobic exercise, group A), and combination group (high-fat diet+curcumin+aerobic exercise, group CuA). Animal model of hepatic steatosis was established by feeding a high-fat diet for 8 weeks. After two weeks of high-fat diet feeding, oral administration of curcumin (400 mg/(kg · d), 5 ml/kg) and/or 70% VO2max aerobic exercise were carried out for six weeks. Rats were euthanized 24 hours after the last exercise, and blood and liver samples were collected. After staining with Oil Red O and Hematoxylin Eosin, observation of lipid deposition, liver tissue morphology, and degree of lipid degeneration in the liver under an optical microscope, observation of autophagosome morphology and quantity in liver cells under a transmission electron microscope. The serum alanine transaminase (ALT) and aspartate transaminase (AST) contents were detected by a biochemical analyzer. Western blotting was used to determine the protein levels of sirtuin1 (SIRT1), forkhead box O1 (FoxO1), acetylated forkhead box O1 (Ac-FoxO1), microtubule-associated protein 1 light chain 3 (LC3), sequestosome 1 protein (P62) and autophagy related protein 7 (ATG7). Results Compared with the M group, the body weight and serum ALT and AST levels of the rats in the Cu, A, and CuA groups were significantly reduced (P<0.01). The number of autophagosomes in the liver was increased, with a significant improvement in lipid deposition in the liver. Hepatic steatosis grading score, lobular inflammation score and the NAFLD activity score (NAS), Ac-FoxO1 and P62 protein expression levels were significantly reduced (P<0.05 or P<0.01). The protein expression levels of SIRT1 and ATG7, as well as the LC3-II/LC3-I protein expression ratio, were significantly increased (P<0.05 or P<0.01), while the protein expression level of FoxO1 showed no significant change (P>0.05). The ratio of Ac-FoxO1/FoxO1 protein expression was significantly reduced in the CuA group (P<0.01), while there was no significant difference in the Cu and A groups (P>0.05).The 2×2 factorial analysis showed that curcumin and aerobic exercise had significant interactive actions on serum ALT and AST levels, hepatic steatosis grading score and NAS scores, as well as liver P62, ATG7, SIRT1, Ac-FoxO1 protein expression. Conclusion Curcumin combined with aerobic exercise can improve liver steatosis and liver injury by promoting FoxO1 deacetylation via activating SIRT1 signaling pathway, inducing autophagy in rats, and the two have a synergistic effect, with joint intervention having a better effect.
Key words
curcumin /
aerobic exercise /
hepatic steatosis /
sirtuin1 (SRIT1) /
forkhead box O1 (FoxO1) /
autophagy
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
References
[1] Kumar R, Priyadarshi RN, Anand U, et al. Non-alcoholic fatty liver disease: growing burden, adverse outcomes and associations[J]. J Clin Transl Hepatol, 2020, 8:76–86.
[2] Song C, Long X, He JB, et al. Recent evaluation about inflammatory mechanisms in nonalcoholic fatty liver disease[J]. Front Pharmacol, 2023, 14: 1081334.
[3] Nassir F.NAFLD: mechanisms, treatments, and biomarkers[J]. Biomolecules, 2022, 12: 824.
[4] Ngu MH, Norhayati MN, Rosnani Z, et al. Curcumin as adjuvant treatment in patients with non-alcoholic fatty liver (NAFLD) disease: a systematic review and meta-analysis[J]. Complement Ther Med, 2022, 68: 102843.
[5] 荆文, 李传芬, 冯连世. 运动激活AMPK改善非酒精性脂肪肝的研究进展[J]. 体育科学, 2019, 39: 91–97.
[6] 刘晓晨, 张社峰, 王改凤. 姜黄素联合有氧运动对糖尿病肝病变和肝中脂肪酸β氧化的影响[J]. 中国比较医学杂志, 2020, 30: 29–35.
[7] Moradi Kelardeh B, Rahmati-Ahmadabad S, Farzanegi P, et al. Effects of non-linear resistance training and curcumin supplementation on the liver biochemical markers levels and structure in older women with non-alcoholic fatty liver disease[J]. J Bodyw Mov Ther, 2020, 24: 154–160.
[8] Ibrahim SG, El-Emam SZ, Mohamed EA, et al. Dimethyl fumarate and curcumin attenuate hepatic ischemia/reperfusion injury via Nrf2/HO-1 activation and anti-inflammatory properties[J]. Int Immunopharmacol, 2020, 80: 106131.
[9] Yeh YW, Wang JJ.Curcumin attenuates hemorrhagic shock and blood replenish resuscitation-induced impairment of pulmonary barrier function by increasing SIRT1 and reducing malondialdehyde and TNF-α contents and neutrophil infiltration in lung in a dose-dependent fashion[J]. Transplantation Proc, 2020, 52: 1875-1879.
[10] Tincopa MA, Loomba R.Non-invasive diagnosis and monitoring of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis[J]. Lancet Gastroenterol Hepatol, 2023, 8:660–670.
[11] Kleiner DE, Brunt EM.Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research[J]. Semin Liver Dis, 2012, 32:3–13.
[12] Farzanegi P, Dana A, Ebrahimpoor Z, et al. Mechanisms of beneficial effects of exercise training on non-alcoholic fatty liver disease (NAFLD): roles of oxidative stress and infammation[J]. Eur J Sport Sci, 2019, 19: 994–1003.
[13] Lai J, Wang HL, Zhang X, et al. Pathologic diagnosis of nonalcoholic fatty liver disease[J]. Arch Pathol Lab Med, 2022, 146:940-946.
[14] Shang Z, Zhang CC, Gao ZL, et al. Quantitative proteomics of HFD-induced fatty liver uncovers novel transcription factors of lipid metabolism[J]. Int J Biol Sci, 2022, 18: 3298–3312.
[15] Wei ZC, Liu N, Tantai XX, et al. The effects of curcumin on the metabolic parameters of non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials[J]. Hepatol Int, 2019, 13: 302–313.
[16] Nam H, Yoo JJ, Cho Y, et al. Effect of exercise-based interventions in nonalcoholic fatty liver disease: a systematic review with meta-analysis[J]. Dig Liver Dis, 2023, 55: 1178–1186.
[17] Badmus OO, Hillhouse SA, Anderson CD, et al. Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways[J]. Clin Sci (Lond), 2022, 136: 1347–1366.
[18] Ramos VM, Kowaltowski AJ, Kakimoto PA.Autophagy in hepatic steatosis: a structured review[J]. Front Cell Dev Biol, 2021, 15; 657389.
[19] Liu PF, Anandhan A, Chen JJ, et al. Decreased autophagosome biogenesis, reduced NRF2, and enhanced ferroptotic cell death are underlying molecular mechanisms of non-alcoholic fatty liver disease[J]. Redox Biol, 2023, 59: 102570.
[20] Zeng JL, Acin-Perez R, Assali EA, et al. Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease[J]. Nat Commun, 2023, 14: 2573.
[21] Zhang XX, Deng YY, Xiang J, et al. Galangin improved non-alcoholic fatty liver disease in mice by promoting autophagy[J]. Drug Des Devel Ther, 2020, 14: 3393-3405.
[22] Greenhill C.The metabolic benefits of exercise-induced hepatic autophagy[J]. Nat Rev Endocrinol, 2023, 19: 254.
[23] Ding XQ, Zhu CY, Wang WH, et al. SIRT1 is a regulator of autophagy: Implications for the progression and treatment of myocardial ischemia-reperfusion[J]. Pharmacol Res, 2024, 199: 106957.
[24] Shan MY, Dai Y, Ren XD, et al. Berberine mitigates nonalcoholic hepatic steatosis by downregulating SIRT1-FoxO1-SREBP2 pathway for cholesterol synthesis [J]. J Integr Med, 2021, 19: 545–554.
[25] Tian C, Huang RR, Xiang M.SIRT1: Harnessing multiple pathways to hinder NAFLD[J]. Pharmacol Res, 2024, 203: 107155.
[26] Hou DY, Liao HT, Hao S, et al. Curcumin simultaneously improves mitochondrial dynamics and myocardial cell bioenergy after sepsis via the SIRT1-DRP1/PGC-1α pathway[J]. Heliyon, 2024, 10: e28501.
[27] 崔红杰, 卢春亭, 潘丽琴, 等. 姜黄素通过SIRT1/FOXO1通路缓解玉米赤霉烯酮诱导的猪肾上皮细胞氧化损伤[J]. 中国农业科学, 2023, 56: 1007–1018.
[28] Salimi A, Kheiripour N, Fathi JA, et al. Nanocurcumin improves lipid status, oxidative stress, and function of the liver in aluminium phosphide-induced toxicity: cellular and molecular mechanisms[J]. Biomed Res Int, 2022, 2022: 7659765.
[29] Juan CG, Matchett KB, Davison GW.A systematic review and meta-analysis of the SIRT1 response to exercise[J]. Sci Rep, 2023, 13: 14752.
[30] Hu ZQ, Zhang HY, Wang YT, et al. Exercise activates Sirt1-mediated Drp1 acetylation and inhibits hepatocyte apoptosis to improve nonalcoholic fatty liver disease[J]. Lipids Health Dis, 2023, 22: 33.
[31] Aziz SG, Pourheydar B, Chodari L, et al. Effect of exercise and curcumin on cardiomyocyte molecular mediators associated with oxidative stress and autophagy in aged male rats[J]. Microvasc Res, 2022, 143: 104380.
[32] Liu J, Xiao Y, Cao L, et al. Insights on E1-like enzyme ATG7: functional regulation and relationships with aging-related diseases[J]. Commun Biol, 2024, 7: 382.
PDF(1873 KB)
