Exercise Intervention Mitigates Pathological Liver Changes in NAFLD Zebrafish by Activating SIRT1/AMPK/NRF2 Signaling

Zou, Yunyi; Chen, Zhanglin; Sun, Chaofen; Yang, Dong Kwon; Zhou, Zuoqiong; Peng, Xiyang; Zheng, Lan; Tang, Changfa

doi:10.3390/ijms222010940

Cited by 36 publications

(26 citation statements)

References 83 publications

(102 reference statements)

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“…Our study results showed that moderate-intensity CT for eight weeks reduced doxorubicin-induced hepatocyte apoptosis in male rats. In line with the findings of our study, Zou et al (17) performing the TUNEL assay also found that 12 weeks of endurance swimming training reduced apoptosis in hepatocytes of zebrafish with nonalcoholic fatty liver disease (NAFLD). Alihemmati et al (18) demonstrated that interval aerobic training mitigated pre-apoptotic indices of Bax/Bcl2 ratio and Bax levels and caspase-6 while increasing Bcl2 levels.…”

Section: Discussionsupporting

confidence: 92%

Continuous Training and Crocin Supplementation Alleviates Doxorubicin-Induced Hepatocyte Apoptosis in Male Rats

et al. 2022

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Background: Chemotherapy drugs can cause liver damage by causing hepatotoxicity. Objectives: This study aimed to determine the interactive effect of continuous training and Crocin supplementation on hepatocyte apoptosis in male rats induced by doxorubicin. Methods: In this experimental study, 40 Wistar rats were randomly assigned to: (1) Healthy, (2) doxorubicin (Dox), (3) Dox + crocin (Cr), (4) Dox + continuous training (CT), and (5) Dox + CT + Cr. Group 1 received normal saline daily; groups 2 to 5 received (7 × 2 mg/kg) Dox intraperitoneal; groups 3 and 5 received 10 mg/kg crocin orally on a daily basis, and groups 4 and 5 were trained 5 days/week (60 - 70 of maximum speed) for 8 weeks. Results: The Dox group had the highest mean percentage of apoptotic hepatocytes (64.33 ± 6.02) compared to other groups (P < 0.05). In contrast, tissue apoptosis was significantly reduced (P < 0.05) in all intervention groups: Dox + CT (30.67 ± 4.04%), Dox + Cr (18 ± 2.64%), and Dox + CT + Cr (13.67 ± 1.52%); however, the improvement was greater in the group receiving crocin. Conclusions: Continuous training, Cr, and their combination significantly reduced hepatocyte apoptosis in male rats exposed to Dox-induced toxicity. However, a greater reduction in liver tissue apoptosis was recorded for the Crocin-treated groups.

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Section: Discussionsupporting

confidence: 92%

Continuous Training and Crocin Supplementation Alleviates Doxorubicin-Induced Hepatocyte Apoptosis in Male Rats

et al. 2022

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“…Exercise reduced NAFLD damage caused by HFD by inhibiting lipolysis and enhancing mitochondrial biosynthesis and fatty acid oxidation, and these changes are the result of activation of cellular pathways mediated through Sirt1 [ 34 ]. In the constructed zebrafish model of NAFLD, swimming exercise improved hepatic steatosis, inflammation, fibrosis and so on caused by HFD, and these beneficial effects were related to activated Sirt1 signaling [ 35 ]. In addition, exercise also alleviates the progression of many diseases by upregulating Sirt1, such as inflammation and metabolic dysfunction of the liver and kidney caused by diabetes [ 36 ], myocardial ischemia/reperfusion injury [ 37 ] and hypothalamic inflammation [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Exercise activates Sirt1-mediated Drp1 acetylation and inhibits hepatocyte apoptosis to improve nonalcoholic fatty liver disease

Zhang

Wang

et al. 2023

Lipids Health Dis

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Purpose Aerobic exercise has shown beneficial effects in the prevention and treatment of non-alcoholic fatty liver disease (NAFLD). Nevertheless, the regulatory mechanism is not turely clear. Therefore, we aim to clarify the possible mechanism by investigating the effects of aerobic exercise on NAFLD and its mitochondrial dysfunction. Methods NAFLD rat model was established by feeding high fat diet. and used oleic acid (OA) to treat HepG2 cells. Changes in histopathology, lipid accumulation, apoptosis, body weight, and biochemical parameters were assessed. In addition, antioxidants, mitochondrial biogenesis and mitochondrial fusion and division were assessed. Results The obtained in vivo results showed that aerobic exercise significantly improved lipid accumulation and mitochondrial dysfunction induced by HFD, activated the level of Sirtuins1 (Srit1), and weakened the acetylation and activity of dynamic-related protein 1 (Drp1). In vitro results showed that activation of Srit1 inhibited OA-induced apoptosis in HepG2 cells and alleviated OA-induced mitochondrial dysfunction by inhibiting Drp1 acetylation and reducing Drp1 expression. Conclusion Aerobic exercise alleviates NAFLD and its mitochondrial dysfunction by activating Srit1 to regulate Drp1 acetylation. Our study clarifies the mechanism of aerobic exercise in alleviating NAFLD and its mitochondrial dysfunction and provides a new method for adjuvant treatment of NAFLD.

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“…The protective effects of MET and/or exercise on hepatocyte apoptosis could be partly attributed to the activation role of AMPK and related antiapoptotic signaling pathways. Recently, Zou et al reported that the underlying mechanisms of alleviating the pathological changes in livers induced by high-fat diets through exercise may be related to SIRT1/AMPK signaling pathways [55]. Zhao et al also showed the important role of an AMPK-caspase-6 axis in regulating liver damage in NASH [56].…”

Section: Discussionmentioning

confidence: 99%

Exercise and Metformin Intervention Prevents Lipotoxicity-Induced Hepatocyte Apoptosis by Alleviating Oxidative and ER Stress and Activating the AMPK/Nrf2/HO-1 Signaling Pathway in db/db Mice

Zhang

Liu

Xiao-Wei

et al. 2022

Oxidative Medicine and Cellular Longevity

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Objective. Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM) commonly coexist and act synergistically to drive adverse clinical outcomes. This study is aimed at investigating the effects of exercise intervention and oral hypoglycaemic drug of metformin (MET) alone or combined on hepatic lipid accumulation. To investigate if oxidative stress and endoplasmic reticulum stress (ERS) are involved in lipotoxicity-induced hepatocyte apoptosis in diabetic mice and whether exercise and/or MET alleviated oxidative stress or ERS-apoptosis by AMPK-Nrf2-HO-1 signaling pathway. Methods. Forty db/db mice with diabetes ( random blood glucose ≥ 250 mg / dL ) were randomly allocated into four groups: control (CON), exercise training alone (EX), metformin treatment alone (MET), and exercise combined with metformin (EM) groups. Hematoxylin-eosin and oil red O staining were carried out to observe hepatic lipid accumulation. Immunohistochemical and TUNEL methods were used to detect the protein expression of the binding immunoglobulin protein (BiP) and superoxide dismutase-1 (SOD1) and the apoptosis level of hepatocytes. ERS-related gene expression and the AMPK-Nrf2-HO-1 signaling pathway were tested by western blotting. Results. Our data showed that db/db mice exhibited increased liver lipid accumulation, which induced oxidative and ER stress of the PERK-eIF2α-ATF4 pathway, and hepatocyte apoptosis. MET combined with exercise training significantly alleviated hepatic lipid accumulation by suppressing BiP expression, the central regulator of ER homeostasis, and its downstream PERK-eIF2α-ATF4 pathway, as well as upregulated the AMPK-Nrf2-HO-1 signaling pathway. Moreover, the combination of exercise and MET displayed protective effects on hepatocyte apoptosis by downregulating Bax expression and TUNEL-positive staining, restoring the balance of cleaved-caspase-3 and caspase-3, and improving the antioxidant defense system to prevent oxidative damage in db/db mice. Conclusion. Compared to MET or exercise intervention alone, the combined exercise and metformin exhibited significant effect on ameliorating hepatic steatosis, inhibiting oxidative and ER stress-induced hepatocyte apoptosis via improving the capacity of the antioxidant defense system and suppression of the PERK-eIF2α-ATF4 pathway. Furthermore, upregulation of AMPK-Nrf2-HO-1 signaling pathway might be a key crosstalk between MET and exercise, which may have additive effects on alleviating hepatic lipid accumulation.

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Exercise Intervention Mitigates Pathological Liver Changes in NAFLD Zebrafish by Activating SIRT1/AMPK/NRF2 Signaling

Cited by 36 publications

References 83 publications

Continuous Training and Crocin Supplementation Alleviates Doxorubicin-Induced Hepatocyte Apoptosis in Male Rats

Continuous Training and Crocin Supplementation Alleviates Doxorubicin-Induced Hepatocyte Apoptosis in Male Rats

Exercise activates Sirt1-mediated Drp1 acetylation and inhibits hepatocyte apoptosis to improve nonalcoholic fatty liver disease

Exercise and Metformin Intervention Prevents Lipotoxicity-Induced Hepatocyte Apoptosis by Alleviating Oxidative and ER Stress and Activating the AMPK/Nrf2/HO-1 Signaling Pathway in db/db Mice

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