Epigenetic Modulation with 5-Aza-CdR Prevents Metabolic-Associated Fatty Liver Disease Promoted by Maternal Overnutrition

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. Methods: 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. Results: 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. Conclusions: 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.