Abstract
BackgroundThe role of Foxo3a in the regulation of autophagy flux and activation of the NLRP3 inflammasome in KCs suffering from HFD conditions is unknown.ResultsUp-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 methodsAutophagy 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.ConclusionsFoxo3a 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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is an increasing hepatic disease with a worldwide distribution [1]
Phosphorylation levels of Foxo3a were significantly up-regulated in Kupffer cells (KCs) treated with LPS and palmitic acid (PA) than in KCs treated with PA or LPS alone; protein levels of Foxo3a were significantly down-regulated in KCs treated with LPS and PA than in KCs treated with PA or LPS alone (Figure 1E)
The upstream regulators of Foxo3a, such as AMPactivated protein kinase (AMPK) and phosphatidyl inositol 3-kinase (PI3K)/AKT were investigated in KCs treated with PA and LPS
Summary
Non-alcoholic fatty liver disease (NAFLD) is an increasing hepatic disease with a worldwide distribution [1]. Pathological processes in NAFLD include excessive accumulation of fat in the liver tissue as well as longlasting and low grade inflammation, which eventually causes steatosis or even more malignant changes [2,3]. Increasing studies have confirmed that liver resident macrophages, Kupffer cells (KCs), mediate inflammation that aggravates the pathological processes of NAFLD [4,5]. The number of KCs is not changed in liver tissue bordering regions of steatohepatitis; fat-laden KCs accelerate inflammatory necrosis via altering their polarization state and activating the myeloid differentiation molecular 88 (MYD88)-dependent Toll-like receptor 4 (TLR4) signaling pathway [6]. Activation of the TLR4 pathway and ROS damage both cue assembly and activation of the nucleotide oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which makes caspase-1 self-cleave to promote the secretion of mature interleukin (IL)-1β and IL-18 [8]. The role of Foxo3a in the regulation of autophagy flux and activation of the NLRP3 inflammasome in KCs suffering from HFD conditions is unknown
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