Developmental retardation in neonates of aldehyde reductase (AKR1A)-deficient mice is associated with low ascorbic acid and high corticosterone levels
Developmental retardation in neonates of aldehyde reductase (AKR1A)-deficient mice is associated with low ascorbic acid and high corticosterone levels
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醛还原酶 (AKR1A) 缺陷小鼠的新生儿发育迟缓与低抗坏血酸和高皮质酮水平有关
DOI：
10.1016/j.jnutbio.2021.108604
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Fujii Junichi
中科院分区：
文献类型：
--
作者：
Ishii Naoki;Homma Takujiro;Takeda Yuji;Aung Naing Ye;Yamada Ken-ichi;Miyata Satoshi;Asao Hironobu;Yamakawa Mitsunori;Fujii Junichi
由Akr1agene编码的醛还原酶催化依赖于NADPH的多种醛化合物的还原，并通过将D-葡萄糖醛酸转化为L-古龙酸而在抗坏血酸(AsA)的生物合成中发挥作用。虽然补充AsA1.5 mg/mL的饮用水可以改善Akr1a−/−(KO)雌性小鼠的生育力，但KO小鼠的产仔数通常比Akr1a+/+(WT)小鼠小，并且大约三分之一的新生儿身高下降。在最小的发育迟缓组中，一半的新生儿在断奶前死亡，剩下的一半(体重不到6克)也几乎没有发育到成年。虽然在胚胎14.5天时，KO和WT小鼠之间的胎儿数量没有发现差异，但KO胚胎的大小已经出现了差异。在这些发育迟缓的KO新生儿30d的器官中，脾和胸腺都很小。当脾细胞检查显示免疫细胞比例正常时，胸腺细胞凋亡性死亡增加，这将导致发育迟缓的KO新生儿胸腺萎缩。尽管他们的母亲已经接受了足够的AsA补充，但小鼠的血浆AsA水平较低，而皮质酮水平则相反地高于野生型小鼠。因此，AsA含量不足和皮质酮代谢缺陷可能是AKR1a基因缺陷小鼠胚胎和新生儿生长迟缓的原因。
Aldehyde reductase encoded by theAkr1agene catalyzes the NADPH-dependent reduction of a variety of aldehyde compounds, and it plays a role in the biosynthesis of ascorbic acid (AsA) by converting D-glucuronate to L-gulonate. Although supplementing drinking water with AsA (1.5 mg/mL) ameliorates the fertility ofAkr1a−/−(KO) female mice, litter sizes in the KO mice are typically smaller than those forAkr1a+/+(WT) mice, and about one-third of the neonates have a reduced stature. Half of the neonates in the smallest, developmentally retarded group died before weaning, and the remaining half (less than 6 g in weight) also barely grew to adulthood. While no difference was found in the number of fetuses between the KO and WT mice at 14.5-embryonic days, the sizes of the KO fetuses had already diverged. Among the organs of these retarded KO neonates at 30 d, the spleen and thymus were characteristically small. While an examination of spleen cells showed the normal proportion of immune cells, apoptotic cell death was increased in the thymus, which would lead to thymic atrophy in the retarded KO neonates. Plasma AsA levels were lower in the small neonates despite the fact that their mothers had received sufficient AsA supplementation, and the corticosterone levels were inversely higher compared to wild-type mice. Thus, insufficient AsA contents together with a defect in corticosterone metabolism might be the cause of the retarded growth of the AKR1A-deficient mice embryos and neonates.