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Food Science and Human Wellness 2023, 12(6): 2390-2407 https://doi.org/10.1016/j.fshw.2023.03.007
Research Article | Open Access | Issue | Published: 04 April 2023

Protective effect of brain and muscle arnt-like protein-1 against ethanol-induced ferroptosis by activating Nrf2 in mice liver and HepG2 cells

Show Author's Information Yanan Zhaoa,  Ranran Zhanga,  Ziheng Chena,  Ziyi Wanga,  Shuang Guana,b( ),  Jing Lua,b( )
College of Food Science and Engineering, Jilin University, Changchun 130062, China
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China

Peer review under responsibility of KeAi Communications Co., Ltd.

Keywords:
Ferroptosis, Alcohol, HepG2 cells, BMAL1, Nrf2, Mice liver
Cite this article:
Zhao Y, Zhang R, Chen Z, et al. Protective effect of brain and muscle arnt-like protein-1 against ethanol-induced ferroptosis by activating Nrf2 in mice liver and HepG2 cells. Food Science and Human Wellness, 2023, 12(6): 2390-2407. https://doi.org/10.1016/j.fshw.2023.03.007
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Abstract Full text About this article

Alcohol abuse has recently become a serious health concern worldwide, and the incidence of alcoholic liver disease (ALD) is rapidly increasing with high morbidity and mortality. Ferroptosis is a newly recognized form of regulated cell death caused by the iron-dependent accumulation of lipid peroxidation. Here we showed that the circadian clock protein BMAL1 in hepatocytes is both necessary and sufficient to protect against ALD by mitigating ferroptosis. Upon exposure to alcohol (5 % Lieber-DeCarli liquid alcohol diet for 10 days before binged alcohol with 5 g/kg body weight in vivo, 300 mmol/L for 12 h in vitro, respectively), the content of iron, reactive oxygen species (ROS) and malondialdehyde (MDA) was boosted significantly while glutathione (GSH) was decreased that mainly based on the downregulated protein expression of ferritin heavy chain (FTH), ferroportin (FPN), heme oxygenase1(HO-1) and anti-cystine/glutamate antiporter (SLC7A11), while these changes could be abolished by ferroptosis inhibitor Ferrostatin-1[Fer-1 (5 mg/kg body weight for 10 days in vivo, 10 μmol/L for 2 h in vitro, respectively)]. Further study indicated that the alcohol could activate the protein expression of brain and muscle arnt-like protein-1 (BMAL1) which exerts a protective effect against ferroptosis through promoting nuclear factor erythroid 2-related factor 2 (Nrf2) translocation into nuclear and subsequently stimulating its downstream proteins FTH, FPN, glutathione peroxidase 4 activity (GPX4), HO-1, SLC7A11, while knockdown of BMAL1 and Nrf2 by RNA interference further downregulated the expression of these protein and thus promoting ferroptosis in response to alcohol. Collectively, our results unveiled that the protective action of BMAL1 during alcohol challenge depends on its ability to activate Nrf2-ARE antiferroptosis pathway and targeting hepatic BMAL1 to dampen hepatic ferroptosis signaling may have therapeutic potential for ALD.


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About this article

Protective effect of brain and muscle arnt-like protein-1 against ethanol-induced ferroptosis by activating Nrf2 in mice liver and HepG2 cells

Show Author's information Yanan Zhaoa, Ranran Zhanga, Ziheng Chena, Ziyi Wanga, Shuang Guana,b( ), Jing Lua,b( )
College of Food Science and Engineering, Jilin University, Changchun 130062, China
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China

Peer review under responsibility of KeAi Communications Co., Ltd.

Abstract

Alcohol abuse has recently become a serious health concern worldwide, and the incidence of alcoholic liver disease (ALD) is rapidly increasing with high morbidity and mortality. Ferroptosis is a newly recognized form of regulated cell death caused by the iron-dependent accumulation of lipid peroxidation. Here we showed that the circadian clock protein BMAL1 in hepatocytes is both necessary and sufficient to protect against ALD by mitigating ferroptosis. Upon exposure to alcohol (5 % Lieber-DeCarli liquid alcohol diet for 10 days before binged alcohol with 5 g/kg body weight in vivo, 300 mmol/L for 12 h in vitro, respectively), the content of iron, reactive oxygen species (ROS) and malondialdehyde (MDA) was boosted significantly while glutathione (GSH) was decreased that mainly based on the downregulated protein expression of ferritin heavy chain (FTH), ferroportin (FPN), heme oxygenase1(HO-1) and anti-cystine/glutamate antiporter (SLC7A11), while these changes could be abolished by ferroptosis inhibitor Ferrostatin-1[Fer-1 (5 mg/kg body weight for 10 days in vivo, 10 μmol/L for 2 h in vitro, respectively)]. Further study indicated that the alcohol could activate the protein expression of brain and muscle arnt-like protein-1 (BMAL1) which exerts a protective effect against ferroptosis through promoting nuclear factor erythroid 2-related factor 2 (Nrf2) translocation into nuclear and subsequently stimulating its downstream proteins FTH, FPN, glutathione peroxidase 4 activity (GPX4), HO-1, SLC7A11, while knockdown of BMAL1 and Nrf2 by RNA interference further downregulated the expression of these protein and thus promoting ferroptosis in response to alcohol. Collectively, our results unveiled that the protective action of BMAL1 during alcohol challenge depends on its ability to activate Nrf2-ARE antiferroptosis pathway and targeting hepatic BMAL1 to dampen hepatic ferroptosis signaling may have therapeutic potential for ALD.

Keywords: Ferroptosis, Alcohol, HepG2 cells, BMAL1, Nrf2, Mice liver

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Received: 20 December 2021
Revised: 19 January 2022
Accepted: 24 February 2022
Published: 04 April 2023
Issue date: November 2023

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