Texas A&M University Not Hispanic or Latino, Texas, United States
Objectives: Recent research has illuminated the pivotal role of DNA methylation in various human ailments, including cancers and imprinting disorders. However, its influence on obesity and the associated metabolic dysfunction-associated fatty liver disease (MAFLD) remains relatively unexplored. This study expands upon prior discoveries linking liver DNA hypermethylation to MAFLD, focusing on assessing the effects of resetting DNA methylation using 5-Aza-CdR, a DNA methylation inhibitor, on obesity and MAFLD.
Methods: Mice were exposed on a high-fat diet (60% fat) for 10 weeks. Starting from week 11, mice were either treated with AZA injection or PBS injection for three weeks. Mice were sacrificed by the end of week 13 for experiments.
Results: The findings indicate that 5-Aza-CdR treatment effectively mitigated weight gain, enhanced glucose tolerance, and reduced hepatic fat accumulation and serum lipid imbalances in high-fat diet-fed mice. Moreover, treated mice exhibited heightened activation of AMPK signaling and increased PPAR-α expression, suggesting improved fatty acid oxidation. Elevated JNK signaling activity in treated mice was associated with the expression alterations of cell apoptosis and proliferation genes. Interestingly, treated mice also showed heightened hepatic inflammation compared to the high-fat diet group, indicating a potential adverse impact on MAFLD management. Importantly, this study identified key differentially expressed apoptotic and inflammatory genes with differentially methylated regions (DMRs) responsive to 5-Aza-CdR treatment, offering valuable insights into potential therapeutic targets.
Conclusions: While this research proposes a promising strategy for obesity and MAFLD management through epigenetic modification, the long-term safety aspects necessitate further investigation.
Funding Sources: This work is supported by NIH/NIDDK 1R01DK112368-01.
