Foxo3a-dependent Bim transcription protects mice from a high fat diet via inhibition of activation of the NLRP3 inflammasome by facilitating autophagy flux in Kupffer cells

Abstract

Background: The role of Foxo3a in the regulation of autophagy flux and activation of the NLRP3 inflammasome in KCs suffering from HFD conditions is unknown. Results: Up-regulation of Foxo3a restored autophagy flux and dampened the activation of the NLRP3 inflammasome in KCs stimulated with PA and LPS. In contrast, down-regulation of Foxo3a increased blockage of autophagy flux and promoted NLRP3 inflammasome activation. Additionally, mRNA levels of Bim were significantly changed with the alteration of Foxo3a in KCs under PA and LPS stimulation among foxo3a targeted genes. Overexpression of Bim restored autophagy influx and attenuated NLRP3 inflammasome pathway activation. In addition, autophagy formation was restored, and activation of NLRP3 inflammasome was inhibited in KCs isolated from mice treated with Iturin A and fed with a HFD. Materials and methods: Autophagy flux in KCs and activation levels of NLRP3 inflammasome were evaluated after altering the expression of Foxo3a in KCs before stimulation with PA and LPS. Additionally, various target genes of Foxo3a were measured in KCs pretreated with an agonist (Iturin A) or inhibitor (SC97) of Foxo3a after KCs stimulation with PA and LPS in order to hunt for targets of Foxo3a. Activation levels of NLRP3 inflammasome in isolated KCs, as well as autophagy flux, were measured after mice were treated with Iturin A and fed with a HFD for 16 weeks. Conclusions: Foxo3a restores autophagy flux and attenuates the activation of the NLRP3 inflammasome by promoting the transcription of Bim, suggesting a potential therapeutic target in NAFLD and other obesity-related diseases.