A1 Journal article (refereed)
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 (2022)

Zhang, Y., Liu, Y., Liu, X., Yuan, X., Xiang, M., Liu, J., Zhang, L., Zhu, S., Lu, J., Tang, Q., & Cheng, S. (2022). 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. Oxidative Medicine and Cellular Longevity, 2022, Article 2297268. https://doi.org/10.1155/2022/2297268

JYU authors or editors

Publication details

All authors or editors: Zhang, Yuan; Liu, Yuting; Liu, Xiaowei; Yuan, Xinmeng; Xiang, Mengqi; Liu, Jingjing; Zhang, Liumei; Zhu, Shouqian; Lu, Jiao; Tang, Qiang; et al.

Journal or series: Oxidative Medicine and Cellular Longevity

ISSN: 1942-0900

eISSN: 1942-0994

Publication year: 2022

Publication date: 09/09/2022

Volume: 2022

Article number: 2297268

Publisher: Hindawi Limited

Publication country: United Kingdom

Publication language: English

DOI: https://doi.org/10.1155/2022/2297268

Publication open access: Openly available

Publication channel open access: Open Access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/83615

Publication is parallel published: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9481363/

Abstract

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.

Keywords: metabolic disorders; non-alcoholic fatty liver disease; adult-onset diabetes; oxidative stress; programmed cell death; exercise therapy; pharmacotherapy; metformin; animal disease models

Contributing organizations

Ministry reporting: Yes

Reporting Year: 2022

JUFO rating: 1