Nutrition Research Institute, University of North Carolina, Chapel Hill, NC, USA.
Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA.
Hum Genomics. 2020 Nov 9;14(1):41. doi: 10.1186/s40246-020-00291-3.
Mitochondrial folate enzyme ALDH1L2 (aldehyde dehydrogenase 1 family member L2) converts 10-formyltetrahydrofolate to tetrahydrofolate and CO 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.
线粒体叶酸酶 ALDH1L2（醛脱氢酶 1 家族成员 L2）可将 10-甲酰四氢叶酸同时转化为四氢叶酸和 CO，并产生 NADPH。我们最近报道，由于复合杂合突变导致该酶缺失与一名男性神经鱼鳞病综合征相关。在此，我们探讨了 ALDH1L2 在细胞代谢中的作用，并强调了该酶调节脂质氧化的机制。
我们构建了 Aldh1l2 敲除（KO）小鼠模型，对其表型、组织病理学以及还原叶酸池水平进行了特征描述，并应用非靶向代谢组学方法来确定肝脏、胰腺和血浆中因酶缺失而导致的代谢变化。我们还使用了 NanoString 小鼠炎症 V2 代码集来分析炎症基因表达，并评估 ALDH1L2 在炎症通路调节中的作用。
雄性和雌性 Aldh1l2 KO 小鼠均存活且未表现出明显的表型。然而，H&E 和油红 O 染色显示，雄性 Aldh1l2 小鼠肝脏中央静脉和门三联体之间的区域脂质小泡堆积，表明脂质代谢异常。代谢组学分析表明，这些小鼠的肝脏和血浆代谢表型发生了巨大变化，提示脂肪酸代谢途径从β-氧化途径转移。具体而言，血浆酰基肉碱和酰基甘氨酸缀合物的显著增加表明肝脏的β-氧化受损。我们的代谢组学数据进一步表明，从机制上讲，ALDH1L2 通过以下步骤调节脂质代谢与辅酶 A 生物合成有关。ALDH1L2 可在线粒体中产生足够的 NADPH，以维持高水平的谷胱甘肽，而谷胱甘肽又需要高水平的半胱氨酸（辅酶 A 的前体）来支持。最终结果是，由于 ALDH1L2 的缺失导致脂质代谢失调，导致线粒体中 ATP 水平降低。
ALDH1L2 的功能对于包括β-氧化、三羧酸循环和胆汁酸生物合成在内的辅酶 A 依赖性途径很重要。该酶缺失与神经皮肤疾病相关的原因与 ALDH1L2 在脂质代谢中的作用有关。更广泛地说，我们的研究将叶酸代谢与脂质稳态和细胞能量平衡的调节联系起来。
