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
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Yan Liu1,3,*, Wenfeng Zhang2,*, Xiaoling Wu1, Jian-Ping Gong2
1Department of Digestive System, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China
2Chongqing Key Laboratory of Hepatobiliary Surgery and Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China
3Department of Gastroenterology, The Fifth People's Hospital of Chengdu, Chengdu, Sichuan, 611130, P.R. China
*These authors contributed equally to this work
Xiaoling Wu, email: email@example.com
Jian-Ping Gong, email: firstname.lastname@example.org
Keywords: Foxo3a, autophagy, NLRP3 inflammasome, Bim, NAFLD
Received: January 23, 2017 Accepted: February 22, 2017 Published: March 06, 2017
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.
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