Department of Pharmacology and Toxicology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
Department of Biosciences University of Salzburg, Salzburg, Austria.
J Lipid Res. 2019 Jul;60(7):1250-1259. doi: 10.1194/jlr.M092593. Epub 2019 May 7.
Exposure to a prenatal high-fat (HF) diet leads to an impaired metabolic phenotype in mouse offspring. The underlying mechanisms, however, are not yet fully understood. Therefore, this study investigated whether the impaired metabolic phenotype may be mediated through altered hepatic DNA methylation and gene expression. We showed that exposure to a prenatal HF diet altered the offspring's hepatic gene expression of pathways involved in lipid synthesis and uptake (SREBP), oxidative stress response [nuclear factor (erythroid-derived 2)-like 2 (Nrf2)], and cell proliferation. The downregulation of the SREBP pathway related to previously reported decreased hepatic lipid uptake and postprandial hypertriglyceridemia in the offspring exposed to the prenatal HF diet. The upregulation of the Nrf2 pathway was associated with increased oxidative stress levels in offspring livers. The prenatal HF diet also induced hypermethylation of transcription factor (TF) binding sites upstream of lipin 1 (), a gene involved in lipid metabolism. Furthermore, DNA methylation of TF binding sites correlated with mRNA expression of These findings suggest that the effect of a prenatal HF diet on the adult offspring's metabolic phenotype are regulated by changes in hepatic gene expression and DNA methylation.
产前高脂肪（HF）饮食暴露会导致小鼠后代代谢表型受损。然而，其潜在机制尚不完全清楚。因此，本研究探讨了产前 HF 饮食暴露是否会通过改变肝脏 DNA 甲基化和基因表达来介导代谢表型受损。研究表明，产前 HF 饮食暴露改变了后代肝脏中参与脂质合成和摄取（SREBP）、氧化应激反应[核因子（红细胞衍生 2）样 2（Nrf2）]和细胞增殖的途径的基因表达。SREBP 途径的下调与先前报道的在产前 HF 饮食暴露的后代中肝脏脂质摄取减少和餐后高甘油三酯血症有关。Nrf2 途径的上调与后代肝脏中氧化应激水平的增加有关。产前 HF 饮食还诱导了与脂质代谢相关的基因 lipin 1（）上游转录因子（TF）结合位点的超甲基化。此外，TF 结合位点的 DNA 甲基化与 mRNA 表达呈正相关。这些发现表明，产前 HF 饮食对成年后代代谢表型的影响是通过肝脏基因表达和 DNA 甲基化的变化来调节的。
