Disruption of hepatic one-carbon metabolism impairs mitochondrial function and enhances macrophage activity in methionine-choline-deficient mice.
Disruption of hepatic one-carbon metabolism impairs mitochondrial function and enhances macrophage activity in methionine-choline-deficient mice.
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肝脏一碳代谢的破坏会损害蛋氨酸胆碱缺陷小鼠的线粒体功能并增强巨噬细胞的活性。
DOI：
10.1016/j.jnutbio.2020.108381
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
daSilva,RobinP
中科院分区：
文献类型：
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作者：
Eudy,BrandonJ;McDermott,CaitlinE;Fernandez,Gabriel;Mathews,ClaytonE;Lai,Jinping;daSilva,RobinP
一碳代谢是支持甲基化的代谢循环的集合，并为嘌呤和胸苷核苷酸的新合成提供一碳结合的叶酸。在脂肪肝疾病的背景下，磷脂酰乙醇胺甲基化形成胆碱已被广泛研究。然而，在肝损伤过程中，单碳代谢在支持核苷酸合成中的作用尚未得到解决。本研究的目的是确定在限制饮食蛋氨酸和胆碱后，单碳代谢的中断如何影响肝脏的核苷酸代谢。小鼠(n=8)饲喂蛋氨酸胆碱缺乏饲料或对照饲料3周。在喂养的最后一周，我们每隔一天给小鼠服用一种已知的腺苷受体拮抗剂四氧嘧啶(0.5 mg/kg)，以探讨腺苷信号在肝损伤中的作用。我们发现，在蛋氨酸和胆碱缺乏的小鼠中，几种肝核苷酸的浓度显著低于对照组(腺嘌呤：13.9±0.7vs.10.1±0.6vs.1.80±0.1vs.1.4±0.1，胸腺嘧啶：0.0122±0.0027vs.0.0059±0.0027 nmol/mg干组织)。四氧嘧啶治疗引起特异性胸苷核苷酸减少，肝脏线粒体含量减少，脂肪性肝炎加重，表现为肝脏脂质含量增加和巨噬细胞形态改变。本研究证实了单碳代谢在肝损伤过程中对新核苷酸合成和线粒体功能的支持作用。
One-carbon metabolism is a collection of metabolic cycles that supports methylation and provides one-carbon bound folates for thede novosynthesis of purine and thymidine nucleotides. The methylation of phosphatidylethanolamine to form choline has been extensively studied in the context of fatty liver disease. However, the role of one-carbon metabolism in supporting nucleotide synthesis during liver damage has not been addressed. The objective of this study is to determine how the disruption of one-carbon metabolism influences nucleotide metabolism in the liver after dietary methionine and choline restriction. Mice (n=8) were fed a methionine–choline-deficient or control diet for 3 weeks. We treated mice with the compound alloxazine (0.5 mg/kg), a known adenosine receptor antagonist, every second day during the final week of feeding to probe the function of adenosine signaling during liver damage. We found that concentrations of several hepatic nucleotides were significantly lower in methionine- and choline-deficient micevs.controls (adenine: 13.9±0.7vs.10.1±0.6, guanine: 1.8±0.1vs.1.4±0.1, thymidine: 0.0122±0.0027vs.0.0059±0.0027 nmol/mg dry tissue). Treatment of alloxazine caused a specific decrease in thymidine nucleotides, decrease in mitochondrial content in the liver and exacerbation of steatohepatitis as shown by the increased hepatic lipid content and altered macrophage morphology. This study demonstrates a role for one-carbon metabolism in supportingde novonucleotide synthesis and mitochondrial function during liver damage.