褪黑素修复暴露于Cd和游离脂肪酸诱导的脂肪毒性的人肝细胞的脂质组

IF 8.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Anna Migni, Desirée Bartolini, Giada Marcantonini, Roccaldo Sardella, Mario Rende, Alessia Tognoloni, Maria Rachele Ceccarini, Francesco Galli
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引用次数: 0

摘要

肝细胞脂毒性是非酒精性脂肪性肝病(NAFLD)病因学的核心,NAFLD是全球肝衰竭和移植的主要原因。长期有毒污染物越来越被认为是NAFLD的环境危险因素。其中包括镉(Cd),一种与其他细胞毒物和代谢刺激物协同作用以诱导脂肪堆积和脂肪毒性的金属。最近的研究表明,褪黑素(MLT)在这种形式的肝细胞脂毒性修复剂中具有很大的潜力。在本研究中,通过脂质组学分析,在未分化的HepaRG细胞中研究了这种MLT效应的分子暗示,HepaRG细胞是一种人肝细胞前细胞系,单独暴露于Cd毒性或与原型游离脂肪酸(FFA),即饱和脂肪酸棕榈酸和单不饱和油酸(分别为OA和PA)联合暴露,以模拟脂肪肝疾病的细胞脂肪毒性条件。Cd暴露与FFAs协同诱导细胞脂肪变性,与OA相比,PA通过增加H2O2产生水平和凋亡性死亡产生更高水平的脂肪毒性。这些影响与细胞脂质组的变化有关,与NAFLD肝脏的变化相似,不同类别的脂质表达不同,包括三酰基甘油(TG)、二酰基甘油和单酰基甘油、磷脂(PL)、鞘脂、酰基肉碱和FA;比较Cd暴露与PA或OA处理的组合,在所有这些类别中观察到特征差异。MLT显著降低了Cd和FFAs单独或联合处理对脂肪毒性标志的影响,也修复了细胞脂质组的大部分改变,包括酯化成TG和PL类的酰基残基的链长和双键数量。这些发现及其生物信息学解释表明,FA代谢的最早酰基延长酶和去饱和酶步骤在MLT的修复作用中起作用;生物化学研究证实了这种解释,确定了SCD1活性的特定作用。这项脂质组学研究揭示了MLT在Cd和ffa诱导的肝细胞脂毒性中的细胞保护机制,强调了该分子对细胞脂质组的修复作用,可能在脂肪肝疾病中具有治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Melatonin Repairs the Lipidome of Human Hepatocytes Exposed to Cd and Free Fatty Acid-Induced Lipotoxicity

Melatonin Repairs the Lipidome of Human Hepatocytes Exposed to Cd and Free Fatty Acid-Induced Lipotoxicity

Hepatocyte lipotoxicity is central to the aetiology of nonalcoholic fatty liver disease (NAFLD), a leading cause of liver failure and transplantation worldwide. Long-lasting toxic pollutants have increasingly been considered as environmental risk factors of NAFLD. These include cadmium (Cd), a metal that synergizes with other cellular toxicants and metabolic stimuli to induce fat build-up and lipotoxicity. Recent studies demonstrated that melatonin (MLT) holds great potential as repairing agent in this form of hepatocyte lipotoxicity. In this study, the molecular hints of this MLT effect were investigated by lipidomics analysis in undifferentiated HepaRG cells, a human pre-hepatocyte cell line, exposed to Cd toxicity either alone or combined with prototypical free fatty acids (FFA), namely the saturated species palmitic acid and the monounsaturated oleic acid (OA and PA, respectively), to simulate the cellular lipotoxicity conditions of fatty liver disease. Cd exposure synergized with FFAs to induce cellular steatosis, and PA produced higher levels of lipotoxicity compared to OA by leading to increased levels of H2O2 production and apoptotic death. These effects were associated with changes of the cellular lipidome, which approximate those of NAFLD liver, with differentially expressed lipids in different classes that included triacylglycerols (TG), di- and mono-acylglycerols, phospholipids (PL), sphingolipids, acylcarnitines and FA; characteristic differences were observed in all these classes comparing the combinations of Cd exposure with PA or OA treatments. MLT significantly reduced the effects of either individual or combinatorial treatments of Cd and FFAs on lipotoxicity hallmarks, also repairing most of the alterations of the cellular lipidome, including those of the chain length and number of double bonds of acyl residues esterified to TG and PL classes. These findings and their bioinformatics interpretation suggest a role for the earliest acyl elongase and desaturase steps of FA metabolism in this repairing effect of MLT; biochemistry studies validated such interpretation identifying a specific role for SCD1 activity. This lipidomics study shed light on the cytoprotective mechanism of MLT in Cd and FFA-induced hepatocyte lipotoxicity, highlighting a repairing effect of this molecule on the cellular lipidome, which may hold therapeutic potential in fatty liver diseases.

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来源期刊
Journal of Pineal Research
Journal of Pineal Research 医学-内分泌学与代谢
CiteScore
17.70
自引率
4.90%
发文量
66
审稿时长
1 months
期刊介绍: The Journal of Pineal Research welcomes original scientific research on the pineal gland and melatonin in vertebrates, as well as the biological functions of melatonin in non-vertebrates, plants, and microorganisms. Criteria for publication include scientific importance, novelty, timeliness, and clarity of presentation. The journal considers experimental data that challenge current thinking and welcomes case reports contributing to understanding the pineal gland and melatonin research. Its aim is to serve researchers in all disciplines related to the pineal gland and melatonin.
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