SIRT3 Regulates H3K9Ac Modification to Affect DDIT4 Involved in Abnormal Hepatic Lipid Metabolism in Male Offspring of Paternal High-Fat Diet

Studies indicate that the male environment and feeding patterns may impact the offspring. In this study, a paternal high-fat diet (HFD) model was established to investigate the lipid metabolism of male offspring. We found that HFD-F1 male mice exhibited abnormal hepatic gluconeogenesis in intraperitoneal pyruvate tolerance test (IPPTT) and increased lipid deposition in the liver. Additionally, the contents of triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) in plasma and liver tissues were significantly elevated in HFD-F1 male mice. Transcriptome analysis revealed upregulation of genes involved in adipogenesis, such as Ddit4, and downregulation of oxidative phosphorylation-related genes like Nmrk1. Western blotting confirmed decreased SIRT3 expression, increased DDIT4 expression, and reduced AKT phosphorylation in the liver of HFD-F1 male mice. In AML12 cells, knockdown of Sirt3 led to increased DDIT4 expression and decreased AKT phosphorylation, while overexpression of Sirt3 had the opposite effect in vitro. Notably, H3K9Ac was significantly elevated in the liver of HFD-F1 male mice. Furthermore, changes in SIRT3 expression influenced the levels of H3K9Ac. ChIP-qPCR assays demonstrated a significant increase in the binding of H3K9Ac to the Ddit4 promoter in HFD-F1 male mice. In conclusion, our findings highlight the role of the SIRT3-H3K9Ac-DDIT4-AKT pathway in mediating abnormal hepatic lipid metabolism in male offspring of paternal HFD. These results provide new mechanistic insights into the epigenetic regulation and the molecular basis of lipid metabolism dysregulation and suggest potential targets for therapeutic intervention.