FUNDC1 insufficiency sensitizes high fat diet intake-induced cardiac remodeling and contractile anomaly through ACSL4-mediated ferroptosis
FUNDC1 insufficiency sensitizes high fat diet intake-induced cardiac remodeling and contractile anomaly through ACSL4-mediated ferroptosis
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DOI：
10.1016/j.metabol.2021.154840
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发表时间：
2021-08-02
影响因子：
9.8
通讯作者：
Ren, Jun
中科院分区：
文献类型：
--
作者：
Pei, Zhaohui;Liu, Yandong;Ren, Jun
目的：缺铁症适用于心血管疾病。鉴于线粒体自噬在铁凋亡的管理中的突出作用以及我们最近在肥胖异常中发现的FUN 14结构域1（FUNDC 1），本研究评估了FUNDC 1缺乏对高脂饮食（HFD）诱导的心脏异常的影响。WT和FUNDC 1（-/-）小鼠在存在铁凋亡抑制剂利司他汀-1（LIP-1，10 mg/kg，i. p.）的情况下喂食HFD（45%卡路里来自脂肪）或低脂饮食（LFD，10%卡路里来自脂肪）10周。结果如下：差异表达基因（DEG）的RNAseq分析报告了肥胖大鼠心脏中与铁凋亡和线粒体自噬相关的基因本体论术语，该术语在肥胖啮齿动物和人类心脏中得到验证。尽管10周HFD摄入没有改变整体代谢、心脏几何结构和功能，但消融FUNDC 1暴露了HFD激发后的代谢紊乱、明显的心脏重塑、收缩、细胞内Ca 2+和线粒体异常，LIP-1减弱或减轻了除整体代谢外的影响。FUNDC 1消融揭示了HFD诱发的脂肪酸合成酶ACSL 4、坏死性凋亡、炎症、铁凋亡、线粒体O-2（-）产生和线粒体损伤的升高，以及抑制自噬和DNA修复酶8-oxoG DNA糖基化酶1（OGG 1），但不包括凋亡，除ACSL 4及其调节剂SP 1外，LIP-1可逆转其作用。在体外数据指出，花生四烯酸，ACSL 4底物，引起细胞色素C释放，心肌细胞缺陷，和脂质过氧化FUNDC 1缺陷下，中断的影响由SP1，ACSL 4和ferroptosis.Conclusions抑制剂：这些数据表明，FUNDC 1缺陷敏化心脏重塑和功能障碍与短期HFD曝光，可能通过ACSL 4介导的调节ferroptosis。(C)2021爱思唯尔公司All rights reserved.
Objective: Ferroptosis is indicated in cardiovascular diseases. Given the prominent role of mitophagy in the governance of ferroptosis and our recent finding for FUN14 domain containing 1 (FUNDC1) in obesity anomalies, this study evaluated the impact of FUNDC1 deficiency in high fat diet (HFD)-induced cardiac anomalies.Methods and materials: WT and FUNDC1(-/-) mice were fed HFD (45% calorie from fat) or low fat diet (LFD, 10% calorie from fat) for 10 weeks in the presence of the ferroptosis inhibitor liproxstatin-1 (LIP-1, 10 mg/kg, i.p.).Results: RNAseq analysis for differentially expressed genes (DEGs) reported gene ontology term related to ferroptosis and mitophagy in obese rat hearts, which was validated in obese rodent and human hearts. Although 10-week HFD intake did not alter global metabolism, cardiac geometry and function, ablation of FUNDC1 unmasked metabolic derangement, pronounced cardiac remodeling, contractile, intracellular Ca2+ and mitochondrial anomalies upon HFD challenge, the effects of which with exception of global metabolism were attenuated or mitigated by LIP-1. FUNDC1 ablation unmasked HFD-evoked rises in fatty acid synthase ACSL4, necroptosis, inflammation, ferroptosis, mitochondrial O-2(-) production, and mitochondrial injury as well as dampened autophagy and DNA repair enzyme 8-oxoG DNA glycosylase 1 (OGG1) but not apoptosis, the effect of which except ACSL4 and its regulator SP1 was reversed by LIP-1. In vitro data noted that arachidonic acid, an ACSL4 substrate, provoked cytochrome C release, cardiomyocyte defect, and lipid peroxidation under FUNDC1 deficiency, the effects were interrupted by inhibitors of SP1, ACSL4 and ferroptosis.Conclusions: These data suggest that FUNDC1 deficiency sensitized cardiac remodeling and dysfunction with short-term HFD exposure, likely through ACSL4-mediated regulation of ferroptosis. (C) 2021 Elsevier Inc. All rights reserved.