Targeting PPARα/γ by icariside II to rescue GalN/LPS-induced acute liver injury in mice: Involvement of SIRT6/NF-κB signaling pathway

Background: Peroxisome proliferator-activated receptor α and-γ (PPARα/γ) are known to play crucial roles in acute liver injury (ALI). Icariside II (ICS II), a natural flavonoid compound derived from Herba EpimedII, confers neuroprotection with PPARα/γ induction potency.

Purpose: This study was aimed to explore whether ICS II has the capacity to protect against ALI, and the role of PPARα/γ in the beneficial effect of ICS II on ALI.

Methods: Mice challenged by D-galactosamine (GalN)/lipopolysaccharide (LPS) and Kupffer cells (KCs) upon LPS insult were used as ALI models in vivo and in vitro. PPARα/γ-deficient mice were treated with ICS II to validate the potential targets of ICS II on ALI.

Results: We found that ICS II (5, 10, 20 mg/kg) dose-dependently improved the survival rate and liver histology, decreased ALT and AST in GalN/LPS-treated mice. Furthermore, ICS II directly bound to PPARα/γ and increased their activities. The protective properties of ICS II were counteracted when PPARα/γ were knocked out in GalN/LPS-induced mice and LPS-induced KCs, respectively. Mechanistically, ICS II restored mitochondrial function, reduced oxidative stress and inflammation through activating PPARα/γ, which activated Sirt6 and inhibited NF-κB nuclear translocation.

Conclusion: Our findings not only highlight PPARα/γ-SIRT6 signaling as a vital therapeutic target to combat ALI, but also reveal ICS II may serve as a novel dual PPARα/γ agonist to safeguard ALI from the oxidation-inflammation vicious circle by mediating SIRT6/NF-κB.