Peng, HuiXu, HuitingWu, JieLi, JiangyuanZhou, YiDing, ZehuanSiwko, Stefan K.Yuan, XianglinSchalinske, Kevin L.Alpini, GianfrancoZhang, Ke K.Xie, Linglin2023-07-102023-07-102021Peng H, Xu H, Wu J, et al. Maternal high-fat diet disrupted one-carbon metabolism in offspring, contributing to nonalcoholic fatty liver disease. Liver Int. 2021;41(6):1305-1319. doi:10.1111/liv.14811https://hdl.handle.net/1805/34258Background & aims: Pregnant women may transmit their metabolic phenotypes to their offspring, enhancing the risk for nonalcoholic fatty liver disease (NAFLD); however, the molecular mechanisms remain unclear. Methods: Prior to pregnancy female mice were fed either a maternal normal-fat diet (NF-group, "no effectors"), or a maternal high-fat diet (HF-group, "persistent effectors"), or were transitioned from a HF to a NF diet before pregnancy (H9N-group, "effectors removal"), followed by pregnancy and lactation, and then offspring were fed high-fat diets after weaning. Offspring livers were analysed by functional studies, as well as next-generation sequencing for gene expression profiles and DNA methylation changes. Results: The HF, but not the H9N offspring, displayed glucose intolerance and hepatic steatosis. The HF offspring also displayed a disruption of lipid homeostasis associated with an altered methionine cycle and abnormal one-carbon metabolism that caused DNA hypermethylation and L-carnitine depletion associated with deactivated AMPK signalling and decreased expression of PPAR-α and genes for fatty acid oxidation. These changes were not present in H9N offspring. In addition, we identified maternal HF diet-induced genes involved in one-carbon metabolism that were associated with DNA methylation modifications in HF offspring. Importantly, the DNA methylation modifications and their associated gene expression changes were reversed in H9N offspring livers. Conclusions: Our results demonstrate for the first time that maternal HF diet disrupted the methionine cycle and one-carbon metabolism in offspring livers which further altered lipid homeostasis. CpG islands of specific genes involved in one-carbon metabolism modified by different maternal diets were identified.en-USPublisher PolicyObesityMethionineSAM transferaseFatty acid oxidationDNA methylationArticle