Figure 11.

The proposed mechanisms by which periodontitis promotes HFD-induced NAFLD progression and imipramine inhibits both periodontitis and NASH in mice with MetS. Our current and previous studies have shown that periodontitis-associated LPS and MetS-related SFA, such as PA, synergistically stimulated ASMase activity in macrophages, leading to increased production of ceramide and S1P and subsequent upregulation of inflammatory cytokines. It is well known that inflammatory cytokines induce insulin resistance and hepatic inflammation, which contribute to NAFLD progression. It is also well known that inflammatory cytokines stimulate matrix metalloproteinases and osteoclastogenesis, which increase periodontal tissue degradation and alveolar bone loss. Therefore, periodontitis promotes NAFLD progression via insulin resistance and hepatic inflammation, but inhibiting ASMase by imipramine reduces ceramide and S1P production and subsequently inhibits the inflammatory cytokine expression, which improves both NAFLD and periodontitis.