Spermidine mitigates ferroptosis in free fatty acid-induced AML-12 cells through the ATF4/SLC7A11/GCLM/GPX4 pathway

IF 3.9 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jia Zhang, Tao Zhang, Yihang Chen, Xiaojie Xuan, Yuqian Zhao, Gaofeng Lu
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Abstract

Non-alcoholic fatty liver disease (NAFLD) is a prominent cause of chronic liver disease worldwide. Spermidine (SPD), a naturally occurring polyamine, has shown potential in alleviating the accumulation of hepatic lipids and reducing NAFLD symptoms in overweight mice. Nonetheless, the specific mechanisms through which SPD exerts its effects remain largely unknown. This study seeks to explore the protective effects of SPD on NAFLD and to clarify the underlying mechanisms. An in vitro model of NAFLD was established by inducing steatosis in AML-12 cells through the use of free fatty acids (FFAs). Our experimental results demonstrate that SPD significantly reduces NAFLD development induced by FFAs. This reduction is primarily achieved through the inhibition of cellular ferroptosis, as evidenced by decreased levels of Fe2+, malondialdehyde (MDA), and reactive oxygen species (ROS). Additionally, SPD was found to enhance cellular activity and ameliorate mitochondrial dysfunction and oxidative stress caused by FFA exposure.

Further mechanistic studies have revealed that SPD upregulates the expression of solute transporter family 7a member 11 (SLC7A11), glutamate-cysteine ligase modifier subunit (GCLM), and glutathione peroxidase (GPX4). This upregulation is mediated by the activation of activating transcription factor 4 (ATF4). Knockdown experiments of ATF4 confirmed that its inhibition reverses the upregulation of SLC7A11, GCLM, and GPX4, thereby negating the protective effects of SPD. In conclusion, our findings suggest that SPD mitigates NAFLD by modulating the ATF4/SLC7A11/GCLM/GPX4 signaling pathway, resulting in the suppression of ferroptosis and the improvement of cellular health. These insights provide a novel molecular mechanism and identify potential therapeutic targets for the treatment of NAFLD.

精胺通过 ATF4/SLC7A11/GCLM/GPX4 通路减轻游离脂肪酸诱导的 AML-12 细胞的铁变态反应
非酒精性脂肪肝(NAFLD)是全球慢性肝病的主要病因。精胺(SPD)是一种天然多胺,在减轻超重小鼠肝脏脂质积累和减轻非酒精性脂肪肝症状方面具有潜力。然而,SPD 发挥作用的具体机制在很大程度上仍不为人所知。本研究旨在探索 SPD 对非酒精性脂肪肝的保护作用,并阐明其潜在机制。通过使用游离脂肪酸(FFAs)诱导 AML-12 细胞发生脂肪变性,建立了非酒精性脂肪肝的体外模型。我们的实验结果表明,SPD 能显著降低游离脂肪酸诱导的非酒精性脂肪肝的发展。这种降低主要是通过抑制细胞铁变态反应来实现的,Fe2+、丙二醛(MDA)和活性氧(ROS)水平的降低就是证明。进一步的机理研究发现,SPD 能上调溶质转运体家族 7a 成员 11(SLC7A11)、谷氨酸-半胱氨酸连接酶修饰亚基(GCLM)和谷胱甘肽过氧化物酶(GPX4)的表达。这种上调是通过激活转录因子 4(ATF4)介导的。敲除 ATF4 的实验证实,抑制 ATF4 可逆转 SLC7A11、GCLM 和 GPX4 的上调,从而抵消 SPD 的保护作用。总之,我们的研究结果表明,SPD可通过调节ATF4/SLC7A11/GCLM/GPX4信号通路缓解非酒精性脂肪肝,从而抑制铁变态反应并改善细胞健康。这些见解提供了一种新的分子机制,并为治疗非酒精性脂肪肝确定了潜在的治疗靶点。
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来源期刊
CiteScore
11.00
自引率
2.10%
发文量
109
审稿时长
53 days
期刊介绍: BBA Molecular and Cell Biology of Lipids publishes papers on original research dealing with novel aspects of molecular genetics related to the lipidome, the biosynthesis of lipids, the role of lipids in cells and whole organisms, the regulation of lipid metabolism and function, and lipidomics in all organisms. Manuscripts should significantly advance the understanding of the molecular mechanisms underlying biological processes in which lipids are involved. Papers detailing novel methodology must report significant biochemical, molecular, or functional insight in the area of lipids.
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