Gestational Leucylation Suppresses Embryonic T‐Box Transcription Factor 5 Signal and Causes Congenital Heart Disease

Dysregulated maternal nutrition, such as vitamin deficiencies and excessive levels of glucose and fatty acids, increases the risk for congenital heart disease (CHD) in the offspring. However, the association between maternal amino‐acid levels and CHD is unclear. Here, it is shown that increased leuc...

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Published in:	Advanced science Vol. 9; no. 15; pp. e2201034 - n/a
Main Authors:	Zhang, Xuan, Liu, Lian, Chen, Wei‐Cheng, Wang, Feng, Cheng, Yi‐Rong, Liu, Yi‐Meng, Lai, Yang‐Fan, Zhang, Rui‐Jia, Qiao, Ya‐Nan, Yuan, Yi‐Yuan, Lin, Yan, Xu, Wei, Cao, Jing, Gui, Yong‐Hao, Zhao, Jian‐Yuan
Format:	Journal Article
Language:	English
Published:	Germany John Wiley & Sons, Inc 01-05-2022 John Wiley and Sons Inc Wiley
Subjects:	Amino acids Animals Cardiovascular disease Congenital diseases congenital heart disease Diabetes Embryos Fetuses gestational amino acid levels Heart Heart Defects, Congenital - genetics Homocysteine Humans Leucine Lysine lysine‐leucylation Metabolism Metabolites Mice NMR Nuclear magnetic resonance Nutrition Plasma Pregnancy Sirtuin 3 T-Box Domain Proteins TBX5 signal Transfer RNA Vitamin B Womens health leucine congenital heart disease lysine-leucylation TBX5 signal gestational amino acid levels
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Summary:	Dysregulated maternal nutrition, such as vitamin deficiencies and excessive levels of glucose and fatty acids, increases the risk for congenital heart disease (CHD) in the offspring. However, the association between maternal amino‐acid levels and CHD is unclear. Here, it is shown that increased leucine levels in maternal plasma during the first trimester are associated with elevated CHD risk in the offspring. High levels of maternal leucine increase embryonic lysine‐leucylation (K‐Leu), which is catalyzed by leucyl‐tRNA synthetase (LARS). LARS preferentially binds to and catalyzes K‐Leu modification of lysine 339 within T‐box transcription factor TBX5, whereas SIRT3 removes K‐Leu from TBX5. Reversible leucylation retains TBX5 in the cytoplasm and inhibits its transcriptional activity. Increasing embryonic K‐Leu levels in high‐leucine‐diet fed or Sirt3 knockout mice causes CHD in the offspring. Targeting K‐Leu using the leucine analogue leucinol can inhibit LARS activity, reverse TBX5 K‐Leu modification, and decrease the occurrence of CHD in high‐leucine‐diet fed mice. This study reveals that increased maternal leucine levels increases CHD risk in the offspring through inhibition of embryonic TBX5 signaling, indicating that leucylation exerts teratogenic effects during heart development and may be an intervening target of CHD. Increased gestational leucine levels are significantly associated with risk for congenital heart disease (CHD) in offspring. Increased embryonic lysine‐leucylation (K‐Leu), generated via maternal high‐leucine‐chow feeding, or Sirt3 knockout, causes CHD in the offspring of mice, through elevating embryonic K‐Leu of TBX5 and inhibiting TBX5 activity. Targeting K‐Leu via leucinol reverses K‐Leu modifications and lowers the occurrence of CHD in mice.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2198-3844 2198-3844
DOI:	10.1002/advs.202201034