Sesamin attenuates liver inflammation caused by PFOS via regulating SAP130-mediated hepatocyte-macrophage crosstalk

BACKGROUND: Perfluorooctane sulfonate (PFOS) is a prototypical persistent organic pollutant that has been linked to liver inflammation. Sesamin (Ses), a major lignan in sesame, has been shown to exhibit health-promoting properties. However, the role and specific mechanism of Ses in PFOS-induced liver inflammation remain largely unclear. PURPOSE: This study aimed to investigate the hepatoprotection and potential mechanism of Ses against PFOS-induced inflammation. METHODS: Wild-type (WT), Mincle knockout (Ko-mincle), and Hepatocyte-specific knockout Foxo1 (Hko-Foxo1) mice were intragastrically administered Ses and/or PFOS (10 mg/kg) for 4 weeks. In vitro, HepG2 cells were pretreated with Ses for 1 h, then exposed to PFOS for 24 h to establish a cell injury model. RESULTS: We revealed that Ses markedly alleviated PFOS-induced liver injury and inflammation, as evidenced by noticeable histopathological improvements, increased cell activity, and alterations in serum liver enzyme and inflammatory factor levels. Moreover, Ses pretreatment reduced the expression of Mincle and the phosphorylation of its downstream targets, SYK and p65, in macrophages. The reducing effect of Ses on liver inflammation in wild-type mice is significantly better than that in Mincle knockout mice. We also found that Ses decreased the expression of spliceosome-associated protein 130 (SAP130) and Foxo1. Further experiments revealed that SAP130 may serve as a mediator between hepatocytes and macrophages. Hepatocyte-specific knockout Foxo1 reduced the release of SAP130 from hepatocytes and inhibited Mincle/Syk signaling activation in macrophages. CONCLUSION: This study demonstrates that Ses protects against PFOS-induced liver inflammation in mice by modulating crosstalk between hepatocytes and macrophages. Those findings support the potential of Ses as a promising natural compound for counteracting liver inflammation.