ORIGINAL RESEARCH article

Front. Pharmacol.

Sec. Gastrointestinal and Hepatic Pharmacology

Volume 16 - 2025 | doi: 10.3389/fphar.2025.1602280

This article is part of the Research TopicMolecular Insights into Fatty Liver Disease: Pathogenesis, Progression, and Therapeutic StrategiesView all articles

Short-term high-fat diet feeding plus acute ethanol binge induced acute liver injury in mice via oxidative stress, inflammation and pyroptosis

Provisionally accepted
Yao DengYao Deng1Xinling ChenXinling Chen1Wenhai GuoWenhai Guo2Yun ChenYun Chen1Luyao XuLuyao Xu1Wenting SuoWenting Suo1Wei LiuWei Liu1Jiaying DaiJiaying Dai1Kangrong WangKangrong Wang1Qiuling LiQiuling Li1Chengqin LuChengqin Lu1Min DaiMin Dai2Jiean XuJiean Xu1Jinwen XuJinwen Xu1He-Quan ZhuHe-Quan Zhu3*Zaoyuan KuangZaoyuan Kuang4*Yaxing ZhangYaxing Zhang1*
  • 1Department of Physiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
  • 2Sun Yat-sen University, Guangzhou, Guangdong Province, China
  • 3Southwest Medical University, Luzhou, Sichuan, China
  • 4Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, China

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Background: Ethanol binge and obesity are the key risk factors for alcohol-related liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), respectively. The human beings have a habit of drinking alcohol and consuming high calorie foods, these two factors often coexist, and thus contributing to the liver injury. However, the mechanisms of a short-term consumption of high-fat diet (HFD) plus alcohol binge-induced acute liver injury are unclear. Methods: Male C57BL/6 mice (aged 8 to 10 weeks) were fed a HFD or HFD Control diet for three days. Then, they received a single dose of ethanol or the same volume of distilled water by oral gavage. Then, the liver damage was evaluated after 9 hours of ethanol gavage. Results: Short-term (3 days) HFD feeding plus ethanol binge significantly aggravated liver injury and steatosis in mice as indicated by Oil Red O staining and H&E staining, the increased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum and hepatic triglyceride (TG) levels. Mechanistically, short-term HFD feeding plus ethanol binge disturbed hepatic redox homeostasis by increasing 3-nitrotyrosine (3-NT), malondialdehyde (MDA) and myeloperoxidase (MPO) levels, while decreasing glutathione (GSH) levels. HFD and alcohol co-consumption also increased hepatic TNF-α, IL-1β and IL-18 via enhancing the phosphorylation of MAPK (ERK1/2, p38 and JNK) and NF-κB. The canonical (Caspase-1 to GSDMD) and non-canonical pyroptosis signaling (Caspase-8/11 to GSDMD, and Caspase-3 to GSDME) further contributed to the acute liver injury. Conclusion: Short-term HFD feeding plus a single dose of ethanol gavage can significantly exacerbate acute liver injury and hepatic fat deposition in mice by enhancing oxidative stress, MAPK and NF-κB signaling, and Caspase-1/8/11-GSDMD and Caspase-3-GSDME pyroptosis signaling.

Keywords: high-fat diet feeding, acute ethanol binge, Oxidative Stress, caspase-1, caspase-8, caspase-11, GSDMD, GSDME

Received: 29 Mar 2025; Accepted: 30 May 2025.

Copyright: © 2025 Deng, Chen, Guo, Chen, Xu, Suo, Liu, Dai, Wang, Li, Lu, Dai, Xu, Xu, Zhu, Kuang and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
He-Quan Zhu, Southwest Medical University, Luzhou, Sichuan, China
Zaoyuan Kuang, Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong Province, China
Yaxing Zhang, Department of Physiology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China

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