Gestational palmitic acid suppresses embryonic GATA-binding protein 4 signaling and causes congenital heart disease

Dysregulated maternal fatty acid metabolism increases the risk of congenital heart disease (CHD) in offspring with an unknown mechanism, and the effect of folic acid fortification in preventing CHD is controversial. Using gas chromatography coupled to either a flame ionization detector or mass spectrometer (GC-FID/MS) analysis, we find that the palmitic acid (PA) concentration increases significantly in serum samples of pregnant women bearing children with CHD. Feeding pregnant mice with PA increased CHD risk in offspring and cannot be rescued by folic acid supplementation. We further find that PA promotes methionyl-tRNA synthetase (MARS) expression and protein lysine homocysteinylation (K-Hcy) of GATA4 and results in GATA4 inhibition and abnormal heart development. Targeting K-Hcy modification by either genetic ablation of Mars or using N-acetyl-L-cysteine (NAC) decreases CHD onset in high-PA-diet-fed mice. In summary, our work links maternal malnutrition and MARS/K-Hcy with the onset of CHD and provides a potential strategy in preventing CHD by targeting K-Hcy other than folic acid supplementation. [Display omitted] •Maternal high palmitic acid is associated with increased risk of CHD in offspring•Palmitic acid promotes MARS and K-Hcy modification through activating NF-κB•GATA4 transcriptional acitivity is inhibited by K-Hcy modification•Inhibition of K-Hcy rescued PA-induced CHD occurrence in mice Zhao et al. report that elevated maternal serum palmitic acid (PA) is associated with the risk of congenital heart disease (CHD) in offspring. PA induces CHD phenotypes in mice via promoting K-Hcy of GATA4, therefore inhibiting its transcriptional activity. Inhibition of K-Hcy rescued PA-induced CHD occurrence.