Sex-Specific Metabolic Effects of Dietary Folate Withdrawal in Wild-Type and Aldh1l1 Knockout Mice.
Sex-Specific Metabolic Effects of Dietary Folate Withdrawal in Wild-Type and Aldh1l1 Knockout Mice.
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DOI：
10.3390/metabo12050454
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发表时间：
2022-05-18
期刊：
影响因子：
4.1
通讯作者：
中科院分区：
文献类型：
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ALDH 1 L1（10-甲酰四氢叶酸脱氢酶）是叶酸代谢的一种酶，在肝脏中高度表达。它通过在NADP+依赖性反应中将10-甲酰四氢叶酸转化为四氢叶酸和CO2来调节叶酸结合的一碳基团的总体通量。我们以前的研究表明，Aldh 1 l1基因敲除（KO）小鼠在喂食含有2 ppm叶酸的标准食物时，肝脏代谢型发生改变，伴有叶酸缺乏的代谢症状。在此，我们对KO和野生型（WT）雄性和雌性小鼠的肝脏和血浆进行了非靶向代谢组学分析，这些小鼠喂食标准或叶酸缺乏饮食16周。OPLS-DA是一种监督多变量技术，分别应用于肝脏和血浆数据集的6595和10，678个特征，表明基因型和饮食单独或组合在两种类型的生物标本中产生不同的代谢谱。基于肝脏和血浆中最可靠的代谢物（OL 1和OL 2a本体水平）对受影响的代谢途径进行的更详细分析表明，膳食叶酸限制本身并不能完全概括KO的代谢作用。值得注意的是，饮食中叶酸的缺乏只会增强与ALDH 1 L1损失相关的代谢紊乱。重要的是，ALDH 1 L1损失和膳食叶酸缺乏都会产生性别特异性代谢效应。
ALDH1L1 (10-formyltetrahydrofolate dehydrogenase), an enzyme of folate metabolism, is highly expressed in the liver. It regulates the overall flux of folate-bound one-carbon groups by converting 10-formyltetrahydrofolate to tetrahydrofolate and CO2 in a NADP+-dependent reaction. Our previous study revealed that Aldh1l1 knockout (KO) mice have an altered liver metabotype with metabolic symptoms of folate deficiency when fed a standard chow diet containing 2 ppm folic acid. Here we performed untargeted metabolomic analysis of liver and plasma of KO and wild-type (WT) male and female mice fed for 16 weeks either standard or folate-deficient diet. OPLS-DA, a supervised multivariate technique that was applied to 6595 and 10,678 features for the liver and plasma datasets, respectively, indicated that genotype and diet, alone or in combination, gave distinct metabolic profiles in both types of biospecimens. A more detailed analysis of affected metabolic pathways based on most confidently identified metabolites in the liver and plasma (OL1 and OL2a ontology level) indicated that the dietary folate restriction itself does not fully recapitulate the metabolic effect of the KO. Of note, dietary folate withdrawal enhanced the metabolic perturbations linked to the ALDH1L1 loss only for a subset of metabolites. Importantly, both the ALDH1L1 loss and dietary folate deficiency produced sex-specific metabolic effects.
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影响因子：
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