Genetic Deficiency of Flavin-Containing Monooxygenase 3 (Fmo3) Protects Against Thrombosis but Has Only a Minor Effect on Plasma Lipid Levels-Brief Report
Genetic Deficiency of Flavin-Containing Monooxygenase 3 (Fmo3) Protects Against Thrombosis but Has Only a Minor Effect on Plasma Lipid Levels-Brief Report
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DOI：
10.1161/atvbaha.119.312592
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发表时间：
2019-06-01
影响因子：
8.7
通讯作者：
Lusis, Aldons J.
中科院分区：
文献类型：
--
作者：
Shih, Diana M.;Zhu, Weifei;Lusis, Aldons J.
目的：FMO(黄素单加氧酶)3将细菌来源的三甲胺转化为三甲胺N氧化物(TMAO)，三甲胺N氧化物是心血管疾病的独立危险因素。我们建立了FMO3基因敲除(FMO3KO)小鼠，以研究其对血浆TMAO、血脂、葡萄糖/胰岛素代谢、血栓形成和动脉粥样硬化的影响。方法和结果-先前在LDLRKO(低密度脂蛋白受体基因敲除)小鼠中针对FMO3的反义寡核苷酸(ASO)基因敲除策略导致TMAO水平和动脉粥样硬化显著降低，但也显示了对血脂、胰岛素和血糖的影响。尽管通过CRISPR/Cas9技术在LDLRKO背景上培育的FMO3KO小鼠确实对TMAO水平表现出类似的影响，但对脂代谢的影响不像ASO基因敲除模型那样明显。这些差异可能是ASO的非靶标效应，也可能是对FMO3缺乏的发育适应。为了区分这些可能性，我们用对照或FMO3 ASO处理野生型和FMO3KO小鼠。在FMO3KO小鼠中，FMO3-ASO治疗导致与野生型小鼠相同程度的降脂作用，表明非靶向效应。饲喂致动脉粥样硬化饲料的LDLRKO小鼠的TMAO水平在野生型和FMO3KO小鼠中都很低，对动脉粥样硬化没有明显的影响。当FMO3KO和野生型小鼠喂饲0.5%胆碱时，FMO3KO显示出TMAO和体内血栓形成潜能的显著降低。结论-FMO3KO显著降低全身TMAO水平和血栓形成潜能。然而，以前观察到的FMO3 ASO对血脂水平的巨大影响似乎部分是由于非靶向效应。可视化概述--本文提供了在线可视化概述。
Objective-FMO (flavin-containing monooxygenase) 3 converts bacterial-derived trimethylamine to trimethylamine N-oxide (TMAO), an independent risk factor for cardiovascular disease. We generated FMO3 knockout (FMO3KO) mouse to study its effects on plasma TMAO, lipids, glucose/insulin metabolism, thrombosis, and atherosclerosis.Approach and Results-Previous studies with an antisense oligonucleotide (ASO) knockdown strategy targeting FMO3 in LDLRKO (low-density lipoprotein receptor knockout) mice resulted in major reductions in TMAO levels and atherosclerosis, but also showed effects on plasma lipids, insulin, and glucose. Although FMO3KO mice generated via CRISPR/Cas9 technology bred onto the LDLRKO background did exhibit similar effects on TMAO levels, the effects on lipid metabolism were not as pronounced as with the ASO knockdown model. These differences could result from either off-target effects of the ASO or from a developmental adaptation to the FMO3 deficiency. To distinguish these possibilities, we treated wild-type and FMO3KO mice with control or FMO3 ASOs. FMO3-ASO treatment led to the same extent of lipid-lowering effects in the FMO3KO mice as the wild-type mice, indicating off-target effects. The levels of TMAO in LDLRKO mice fed an atherogenic diet are very low in both wild-type and FMO3KO mice, and no significant effect was observed on atherosclerosis. When FMO3KO and wild-type mice were maintained on a 0.5% choline diet, FMO3KO showed a marked reduction in both TMAO and in vivo thrombosis potential.Conclusions-FMO3KO markedly reduces systemic TMAO levels and thrombosis potential. However, the previously observed large effects of an FMO3 ASO on plasma lipid levels appear to be due partly to off-target effects. Visual Overview-An online visual overview is available for this article.