Maternal high-fat diet orchestrates offspring hepatic cholesterol metabolism via MEF2A hypermethylation-mediated CYP7A1 suppression

作者：Ling Zhang, Wenyu Zou, Shixuan Zhang, Honghua Wu, Ying Gao, Junqing Zhang, Jia Zheng · 发表于：Cellular & Molecular Biology Letters · 年份：2024 · DOI：10.1186/s11658-024-00673-8 · 被引用次数：18 · 研究领域：Birth, Development, and Health、Cholesterol and Lipid Metabolism、Epigenetics and DNA Methylation

BACKGROUND: Maternal overnutrition, prevalent among women of childbearing age, significantly impacts offspring health throughout their lifetime. While DNA methylation of metabolic-related genes mediates the transmission of detrimental effects from maternal high-fat diet (HFD), its role in programming hepatic cholesterol metabolism in offspring, particularly during weaning, remains elusive. METHODS: Female C57BL/6 J mice were administered a HFD or control diet, before and during, gestation and lactation. Hepatic cholesterol metabolism genes in the liver of offspring were evaluated in terms of their expression. The potential regulator of cholesterol metabolism in the offspring's liver was identified, and the function of the targeted transcription factor was evaluated through in vitro experiments. The methylation level of the target transcription factor was assessed using the MassARRAY EpiTYPER platform. To determine whether transcription factor expression is influenced by DNA methylation, in vitro experiments were performed using 5-azacitidine and Lucia luciferase activity assays. RESULTS: Here, we demonstrate that maternal HFD results in higher body weight and hypercholesterolemia in the offspring as early as weaning age. Maternal HFD feeding exacerbates hepatic cholesterol accumulation in offspring primarily by inhibiting cholesterol elimination to bile acids, with a significant decrease of hepatic cholesterol 7α-hydroxylase (CYP7A1). RNA-seq analysis identified myocyte enhan...