Ppad Carried By Omvs Exacerbated Masld Through Npas2/Cyp4a10 Pathway

This study investigated the causal link between periodontitis and metabolic dysfunction-associated steatotic liver disease (MASLD), with a specific focus on how P. gingivalis OMVs mediate hepatic lipid dysregulation through PPAD enzymatic activity. A case-control study compared 92 patients (healthy/Stage I-II vs Stage III-IV periodontitis) to assess MASLD prevalence, following approval by the institution's Ethics Committee (K2024042). Male C57BL/6J mice fed a high-fat diet received P. gingivalis inoculation, with subsequent quantification of serum/hepatic triglycerides, histopathological evaluation (H&E), and dual-stain analysis of lipid deposition (Oil Red O) and fibrosis (Masson). MASLD mice and AML12 cells were treated with P. gingivalis wild-type/Δppad/ppad-oe OMVs to investigate PPAD's influence.This protocol was approved by the Institutional Animal Care and Use Committee (CMU2023004). Clinical analyses revealed a positive correlation between periodontal disease severity and the fatty liver index (OR = 6.18, 95% CI: 2.36-16.13), a predictor of MASLD. P. gingivalis-induced periodontitis exacerbated MASLD progression in obese mice through OMVs that exhibited liver-specific accumulation and amplifying lipid deposition. Mechanistic studies using Δppad/ppad-oe genetic models revealed PPAD-enriched OMVs disrupt hepatic metabolism via NPAS2/CYP4A10 axis suppression, establishing a novel oral-liver signaling pathway. PPAD-derived OMVs exacerbated MASLD progression via the circadian regulator NPAS2/CYP4A10 axis. These findings establish a mechanistic link between periodontitis and hepatic lipid dysregulation, implicating chronic inflammation in metabolic pathogenesis while suggesting therapeutic potential through OMV-targeted interventions.