Aldh1l2 knockout mouse metabolomics links the loss of the mitochondrial folate enzyme to deregulation of a lipid metabolism observed in rare human disorder.
Aldh1l2 knockout mouse metabolomics links the loss of the mitochondrial folate enzyme to deregulation of a lipid metabolism observed in rare human disorder.
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DOI：
10.1186/s40246-020-00291-3
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发表时间：
2020-11-09
期刊：
影响因子：
4.5
通讯作者：
Krupenko SA
中科院分区：
文献类型：
--
作者：
Krupenko NI;Sharma J;Pediaditakis P;Helke KL;Hall MS;Du X;Sumner S;Krupenko SA
线粒体叶酸酶ALDH 1 L2（醛脱氢酶1家族成员L2）将10-甲酰四氢叶酸转化为四氢叶酸和CO2，同时产生NADPH。我们最近报道，缺乏酶由于复合杂合突变与神经鱼鳞病综合征的男性患者。在这里，我们解决ALDH 1 L2在细胞代谢中的作用，并强调该酶调节脂质氧化的机制。我们生成了Aldh 1 l2敲除（KO）小鼠模型，表征了其表型、组织组织学和还原叶酸池水平，并应用非靶向代谢组学来确定由酶损失引起的肝脏、胰腺和血浆中的代谢变化。我们还使用NanoString小鼠炎症V2代码集来分析炎症基因表达，并评估ALDH 1 L2在炎症途径调节中的作用。雄性和雌性Aldh 1 l2 KO小鼠均存活，未显示明显的表型。然而，H&E和油红O染色显示位于Aldh 1 l2-/-雄性小鼠肝脏中央静脉和门静脉三联体之间的脂质囊泡积聚，表明脂质代谢异常。代谢组学分析显示，这些小鼠的肝脏和血浆中的代谢型发生了巨大变化，表明脂肪酸从β-氧化中排出。具体而言，血浆酰基肉毒碱和酰基甘氨酸结合物的急剧增加表明肝脏中的β-氧化受损。我们的代谢组学数据进一步表明，在机制上，ALDH 1 L2对脂质代谢的调节通过以下步骤与辅酶A生物合成相关。ALDH 1 L2能够在线粒体中产生足够的NADPH，以维持高水平的谷胱甘肽，这反过来又是支持高水平的半胱氨酸（辅酶A前体）所必需的。作为最终结果，由于ALDH 1 L2损失导致脂质代谢失调导致线粒体中ATP水平降低。ALDH 1 L2功能对于CoA依赖性途径包括β-氧化、TCA循环和胆汁酸生物合成是重要的。ALDH 1 L2在脂质代谢中的作用解释了为什么这种酶的丢失与神经皮肤疾病有关。在更广泛的范围内，我们的研究将叶酸代谢与细胞内脂质稳态和能量平衡的调节联系起来。在线版本包含补充材料，可通过10.1186/s40246-020-00291-3获得。
Mitochondrial folate enzyme ALDH1L2 (aldehyde dehydrogenase 1 family member L2) converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 simultaneously producing NADPH. We have recently reported that the lack of the enzyme due to compound heterozygous mutations was associated with neuro-ichthyotic syndrome in a male patient. Here, we address the role of ALDH1L2 in cellular metabolism and highlight the mechanism by which the enzyme regulates lipid oxidation. We generated Aldh1l2 knockout (KO) mouse model, characterized its phenotype, tissue histology, and levels of reduced folate pools and applied untargeted metabolomics to determine metabolic changes in the liver, pancreas, and plasma caused by the enzyme loss. We have also used NanoString Mouse Inflammation V2 Code Set to analyze inflammatory gene expression and evaluate the role of ALDH1L2 in the regulation of inflammatory pathways. Both male and female Aldh1l2 KO mice were viable and did not show an apparent phenotype. However, H&E and Oil Red O staining revealed the accumulation of lipid vesicles localized between the central veins and portal triads in the liver of Aldh1l2-/- male mice indicating abnormal lipid metabolism. The metabolomic analysis showed vastly changed metabotypes in the liver and plasma in these mice suggesting channeling of fatty acids away from β-oxidation. Specifically, drastically increased plasma acylcarnitine and acylglycine conjugates were indicative of impaired β-oxidation in the liver. Our metabolomics data further showed that mechanistically, the regulation of lipid metabolism by ALDH1L2 is linked to coenzyme A biosynthesis through the following steps. ALDH1L2 enables sufficient NADPH production in mitochondria to maintain high levels of glutathione, which in turn is required to support high levels of cysteine, the coenzyme A precursor. As the final outcome, the deregulation of lipid metabolism due to ALDH1L2 loss led to decreased ATP levels in mitochondria. The ALDH1L2 function is important for CoA-dependent pathways including β-oxidation, TCA cycle, and bile acid biosynthesis. The role of ALDH1L2 in the lipid metabolism explains why the loss of this enzyme is associated with neuro-cutaneous diseases. On a broader scale, our study links folate metabolism to the regulation of lipid homeostasis and the energy balance in the cell. The online version contains supplementary material available at 10.1186/s40246-020-00291-3.
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影响因子：
5.1
作者：
Krupenko, Natalia I.;Holmes, Roger S.;Tsybovsky, Yaroslav;Krupenko, Sergey A.
通讯作者：
Krupenko, Sergey A.
影响因子：
4.5
作者：
Bjørndal B;Alterås EK;Lindquist C;Svardal A;Skorve J;Berge RK
通讯作者：
Berge RK
影响因子：
3.8
作者：
Jagadeeshaprasad MG;Batkulwar KB;Meshram NN;Tiwari S;Korwar AM;Unnikrishnan AG;Kulkarni MJ
通讯作者：
Kulkarni MJ
影响因子：
3.7
作者：
Khan, Qasim A.;Pediaditakis, Peter;Krupenko, Sergey A.
通讯作者：
Krupenko, Sergey A.
影响因子：
6
作者：
da Silva, Robin P.;Kelly, Karen B.;Al Rajabi, Ala;Jacobs, Rene L.
通讯作者：
Jacobs, Rene L.