Nobiletin protects against alcohol-induced mitochondrial dysfunction and liver injury by regulating the hepatic NRF1-TFAM signaling pathway.

IF 5.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Redox Report Pub Date : 2024-12-01 Epub Date: 2024-09-02 DOI:10.1080/13510002.2024.2395779
Dan Lu, Aiping Huang, Xiaoqing Tong, Xiaoyan Zhang, Songtao Li, Xiaolong Yu
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引用次数: 0

Abstract

Objectives: Alcohol and its metabolites, such as acetaldehyde, induced hepatic mitochondrial dysfunction play a pathological role in the development of alcohol-related liver disease (ALD).

Methods: In this study, we investigated the potential of nobiletin (NOB), a polymethoxylated flavone, to counter alcohol-induced mitochondrial dysfunction and liver injury.

Results: Our findings demonstrate that NOB administration markedly attenuated alcohol-induced hepatic steatosis, endoplasmic reticulum stress, inflammation, and tissue damage in mice. NOB reversed hepatic mitochondrial dysfunction and oxidative stress in both alcohol-fed mice and acetaldehyde-treated hepatocytes. Mechanistically, NOB restored the reduction of hepatic mitochondrial transcription factor A (TFAM) at both mRNA and protein levels. Notably, the protective effects of NOB against acetaldehyde-induced mitochondrial dysfunction and cell death were abolished in hepatocytes lacking Tfam. Furthermore, NOB administration reinstated the levels of hepatocellular NRF1, a key transcriptional regulator of TFAM, which were decreased by alcohol and acetaldehyde exposure. Consistent with these findings, hepatocyte-specific overexpression of Nrf1 protected against alcohol-induced hepatic Tfam reduction, mitochondrial dysfunction, oxidative stress, and liver injury.

Conclusions: Our study elucidates the involvement of the NRF1-TFAM signaling pathway in the protective mechanism of NOB against chronic-plus-binge alcohol consumption-induced mitochondrial dysfunction and liver injury, suggesting NOB supplementation as a potential therapeutic strategy for ALD.

金没药通过调节肝脏 NRF1-TFAM 信号通路,防止酒精诱导的线粒体功能障碍和肝损伤。
研究目的酒精及其代谢产物(如乙醛)诱导的肝线粒体功能障碍在酒精相关性肝病(ALD)的发病中起着病理作用:在这项研究中,我们探讨了金没药(NOB)--一种多甲氧基黄酮--对抗酒精诱导的线粒体功能障碍和肝损伤的潜力:结果:我们的研究结果表明,服用 NOB 能明显减轻酒精诱导的小鼠肝脏脂肪变性、内质网应激、炎症和组织损伤。NOB 逆转了酒精喂养小鼠和乙醛处理肝细胞的肝线粒体功能障碍和氧化应激。从机理上讲,NOB 在 mRNA 和蛋白质水平上恢复了肝线粒体转录因子 A(TFAM)的减少。值得注意的是,在缺乏 Tfam 的肝细胞中,NOB 对乙醛诱导的线粒体功能障碍和细胞死亡的保护作用消失了。此外,NOB 还能恢复肝细胞 NRF1 的水平,NRF1 是 TFAM 的一个关键转录调节因子,酒精和乙醛暴露会降低 NRF1 的水平。与这些发现一致的是,肝细胞特异性过表达 Nrf1 可防止酒精诱导的肝脏 Tfam 减少、线粒体功能障碍、氧化应激和肝损伤:我们的研究阐明了NRF1-TFAM信号通路参与NOB对慢性加暴饮暴食酒精诱导的线粒体功能障碍和肝损伤的保护机制,建议将补充NOB作为ALD的一种潜在治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Redox Report
Redox Report 生物-生化与分子生物学
CiteScore
6.10
自引率
0.00%
发文量
28
审稿时长
>12 weeks
期刊介绍: Redox Report is a multidisciplinary peer-reviewed open access journal focusing on the role of free radicals, oxidative stress, activated oxygen, perioxidative and redox processes, primarily in the human environment and human pathology. Relevant papers on the animal and plant environment, biology and pathology will also be included. While emphasis is placed upon methodological and intellectual advances underpinned by new data, the journal offers scope for review, hypotheses, critiques and other forms of discussion.
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