Department of Nutrition, Texas A&M University, College Station, TX, USA.
Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Liver Int. 2021 Jun;41(6):1305-1319. doi: 10.1111/liv.14811. Epub 2021 Feb 16.
BACKGROUND & 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.
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.
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.
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.
孕妇可能将其代谢表型传递给后代，从而增加非酒精性脂肪性肝病（NAFLD）的风险；然而，其分子机制尚不清楚。
在怀孕前，雌性小鼠分别喂食母体正常脂肪饮食（NF 组，“无效应器”）、母体高脂肪饮食（HF 组，“持续效应器”）或在怀孕前从 HF 饮食过渡到 NF 饮食（H9N 组，“效应器去除”），然后进行怀孕和哺乳，随后断奶后给后代喂食高脂肪饮食。通过功能研究以及下一代测序对基因表达谱和 DNA 甲基化变化分析后代肝脏。
HF 后代而非 H9N 后代表现出葡萄糖不耐受和肝脂肪变性。HF 后代还表现出脂质稳态紊乱，与蛋氨酸循环改变和一碳代谢异常相关，导致 DNA 过度甲基化和 L-肉碱耗竭，与 AMPK 信号转导失活和脂肪酸氧化基因表达降低有关。这些变化在 H9N 后代中不存在。此外，我们鉴定了母体 HF 饮食诱导的与 HF 后代 DNA 甲基化修饰相关的一碳代谢相关基因。重要的是，H9N 后代肝脏中的 DNA 甲基化修饰及其相关基因表达变化得到了逆转。
我们的研究结果首次表明，母体 HF 饮食破坏了后代肝脏中的蛋氨酸循环和一碳代谢，进而改变了脂质稳态。鉴定了不同母体饮食修饰的涉及一碳代谢的特定基因的 CpG 岛。
