过量铁通过激活黄嘌呤氧化酶增强嘌呤代谢，并损害哺乳期仔猪海马的髓鞘形成。

Excess Iron Enhances Purine Catabolism Through Activation of Xanthine Oxidase and Impairs Myelination in the Hippocampus of Nursing Piglets.

机构信息

Department of Nutrition, University of California, Davis, Davis, CA, USA.

Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, Hunan, China.

出版信息

J Nutr. 2019 Nov 1;149(11):1911-1919. doi: 10.1093/jn/nxz166.

DOI:10.1093/jn/nxz166

PMID:31373370

Abstract

BACKGROUND

Few studies have addressed the risk of nutritional iron overexposure in infancy. We previously found that excess dietary iron in nursing piglets resulted in iron overload in the liver and hippocampus and diminished socialization with novel conspecifics in a test for social novelty preference.

OBJECTIVES

This experiment aimed to identify metabolites and metabolic pathways affected by iron overload in the liver and hippocampus of nursing piglets.

METHODS

Liver and hippocampal tissues collected from 22-d-old piglets (Hampshire × Yorkshire crossbreed; 5.28 ± 0.53 kg body weight; 50% male) that received orally 0 (NI group) or 50 mg iron/(d · kg body weight) (HI group) from postnatal day (PD) 2 to PD21 were analyzed for mRNA and protein expression and enzyme activity of xanthine oxidase (XO). Untargeted metabolomics was performed using GC-MS. Expression of myelin basic protein (MBP) in the hippocampus was determined using western blot.

RESULTS

There were 108 and 126 metabolites identified in the hippocampus and liver, respectively. Compared with NI, HI altered 15 metabolites (P < 0.05, q < 0.2) in the hippocampus, including a reduction in myo-inositol (0.86-fold) and N-acetylaspartic acid (0.84-fold), 2 metabolites important for neuronal function and myelination. Seven metabolites involved in purine and pyrimidine metabolism (e.g., hypoxanthine, xanthine, and β-alanine) were coordinately changed in the hippocampus (P < 0.05, q < 0.2), suggesting that iron excess enhanced purine catabolism. The mRNA expression (2.3-fold) (P < 0.05) and activity of XO, a rate-limiting enzyme in purine degradation, was increased. Excess iron increased hippocampal lipid peroxidation by 74% (P < 0.05) and decreased MBP by 44% (P = 0.053). The hepatic metabolome was unaffected.

CONCLUSIONS

In nursing piglets, excess iron enhances hippocampal purine degradation through activation of XO, which may induce oxidative stress and alter energy metabolism in the developing brain.

摘要

背景

很少有研究探讨婴儿时期营养性铁过量暴露的风险。我们之前发现，哺乳期仔猪摄入过量膳食铁会导致肝脏和海马中铁过载，并在社交新颖性偏好测试中减少对新同类的社交。

目的

本实验旨在确定铁过载对哺乳期仔猪肝脏和海马中受影响的代谢物和代谢途径。

方法

从 22 日龄（汉普夏×约克夏杂交；5.28±0.53kg 体重；50%雄性）仔猪采集肝脏和海马组织，这些仔猪从出生后第 2 天（PD）到第 21 天（PD）每天口服 0（NI 组）或 50mg 铁/（d·kg 体重）（HI 组）。使用 GC-MS 进行非靶向代谢组学分析。用 Western blot 法测定海马髓鞘碱性蛋白（MBP）的表达。

结果

分别在海马和肝脏中鉴定出 108 和 126 种代谢物。与 NI 相比，HI 改变了海马中 15 种代谢物（P<0.05，q<0.2），包括肌醇（0.86 倍）和 N-乙酰天冬氨酸（0.84 倍）的减少，这两种代谢物对神经元功能和髓鞘形成很重要。7 种参与嘌呤和嘧啶代谢的代谢物（如次黄嘌呤、黄嘌呤和β-丙氨酸）在海马中协同变化（P<0.05，q<0.2），提示铁过量增强了嘌呤分解代谢。限速酶黄嘌呤氧化酶（XO）的 mRNA 表达（2.3 倍）（P<0.05）和活性增加。过量的铁使海马脂质过氧化增加了 74%（P<0.05），MBP 减少了 44%（P=0.053）。肝代谢组不受影响。