Cheng Henghui, Wu Jie, Peng Hui, Li Jiangyuan, Liu Zhimin, Wang Xian, Zhang Ke, Xie Linglin
Department of Nutrition, Texas A&M University, College Station, TX 77843, USA.
Center for Epigenetics & Disease Prevention, Institute of Biosciences & Technology, College of Medicine, Texas A&M University, Houston, TX 77030, USA.
Nutrients. 2024 Dec 30;17(1):106. doi: 10.3390/nu17010106.
BACKGROUND/OBJECTIVES: This study builds on previous findings from mouse models, which showed that maternal overnutrition induced by a high-fat diet (HFD) promotes metabolic-associated fatty liver disease (MAFLD) in offspring, linked to global DNA hypermethylation. We explored whether epigenetic modulation with 5-Aza-CdR, a DNA methylation inhibitor, could prevent MAFLD in offspring exposed to maternal overnutrition.
The offspring mice from dams of maternal overnutrition were fed either a chow diet or a high-fat diet (HFD) for 10 weeks. These mice were randomly divided into two groups: HFD, and AZA + HFD. Mice assigned to the AZA group were given 5-Aza-CdR during the last three weeks.
Our findings show that 5-Aza-CdR treatment in HFD-fed offspring effectively countered weight gain, improved glucose regulation, and minimized hepatic fat buildup along with serum lipid imbalances. Additionally, it boosted AMPK signaling and raised PPAR-α expression, pointing to enhanced fatty acid oxidation. We also detected an increase in JNK signaling, affecting the gene expression associated with cell death and proliferation. Notably, treated mice displayed more hepatic inflammation than the HFD group alone, suggesting a complex, dual impact on MAFLD management. Significant apoptotic and inflammatory gene changes were identified, along with corresponding differentially methylated regions triggered by 5-Aza-CdR, marking potential therapeutic targets.
5-Aza-CdR was shown to mitigate MAFLD features in offspring of maternal overnutrition by reversing DNA hypermethylation and improving metabolic pathways, though its dual impact on inflammation highlights the need for further research to optimize its therapeutic potential.
背景/目的：本研究基于先前小鼠模型的研究结果，该研究表明高脂饮食（HFD）诱导的母体营养过剩会促进后代发生代谢相关脂肪性肝病（MAFLD），这与全基因组DNA高甲基化有关。我们探讨了使用DNA甲基化抑制剂5-氮杂胞苷（5-Aza-CdR）进行表观遗传调控是否可以预防暴露于母体营养过剩的后代发生MAFLD。
将母体营养过剩的母鼠所产的后代小鼠喂食普通饲料或高脂饮食（HFD）10周。这些小鼠被随机分为两组：HFD组和AZA + HFD组。分配到AZA组的小鼠在最后三周给予5-氮杂胞苷。
我们的研究结果表明，在喂食HFD的后代中进行5-氮杂胞苷治疗可有效对抗体重增加，改善血糖调节，并使肝脏脂肪堆积以及血清脂质失衡最小化。此外，它增强了AMPK信号传导并提高了PPAR-α表达，表明脂肪酸氧化增强。我们还检测到JNK信号传导增加影响与细胞死亡和增殖相关的基因表达。值得注意的是，接受治疗的小鼠比单独的HFD组表现出更多的肝脏炎症，这表明对MAFLD管理有复杂的双重影响。鉴定出显著的凋亡和炎症基因变化，以及由5-氮杂胞苷触发的相应差异甲基化区域，这标志着潜在的治疗靶点。
5-氮杂胞苷通过逆转DNA高甲基化和改善代谢途径减轻了母体营养过剩后代的MAFLD特征，尽管其对炎症的双重影响突出了需要进一步研究以优化其治疗潜力。
