Sharma Jaspreet, Rushing Blake R, Hall Madeline S, Helke Kristi L, McRitchie Susan L, Krupenko Natalia I, Sumner Susan J, Krupenko Sergey A
Nutrition Research Institute, UNC Chapel Hill, Kannapolis, NC 28081, USA.
Department of Nutrition, UNC Chapel Hill, Chapel Hill, NC 27599, USA.
Metabolites. 2022 May 18;12(5):454. doi: 10.3390/metabo12050454.
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 CO in a NADP-dependent reaction. Our previous study revealed that 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.
醛脱氢酶1家族成员L1（10-甲酰四氢叶酸脱氢酶）是一种叶酸代谢酶，在肝脏中高度表达。它通过在依赖烟酰胺腺嘌呤二核苷酸磷酸（NADP）的反应中将10-甲酰四氢叶酸转化为四氢叶酸和一氧化碳，调节与叶酸结合的一碳基团的整体通量。我们之前的研究表明，敲除（KO）小鼠在喂食含2 ppm叶酸的标准饲料时，肝脏代谢型会发生改变，并出现叶酸缺乏的代谢症状。在此，我们对喂食标准或叶酸缺乏饮食16周的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。正交偏最小二乘法判别分析（OPLS-DA）是一种有监督的多元技术，分别应用于肝脏和血浆数据集的6595个和10678个特征，结果表明，基因型和饮食单独或联合作用，在两种生物样本中均产生了不同的代谢谱。基于肝脏和血浆中最可靠鉴定的代谢物（OL1和OL2a本体水平）对受影响的代谢途径进行更详细的分析表明，饮食中叶酸限制本身并不能完全重现KO的代谢效应。值得注意的是，饮食中叶酸缺乏仅对一部分代谢物增强了与ALDH1L1缺失相关的代谢紊乱。重要的是，ALDH1L1缺失和饮食中叶酸缺乏均产生了性别特异性的代谢效应。
