Peroxisome Proliferator-Activated Receptor δ Regulates Inflammation via NF-κB Signaling in Polymicrobial Sepsis

Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center and College of Medicine, University of Cincinnati, Cincinnati, Ohio 45229, USA.
American Journal Of Pathology (Impact Factor: 4.59). 10/2010; 177(4):1834-47. DOI: 10.2353/ajpath.2010.091010
Source: PubMed


The nuclear peroxisome proliferator-activated receptor δ (PPARδ) is an important regulator of lipid metabolism. In contrast to its known effects on energy homeostasis, its biological role on inflammation is not well understood. We investigated the role of PPARδ in the modulation of the nuclear factor-κB (NF-κB)-driven inflammatory response to polymicrobial sepsis in vivo and in macrophages in vitro. We demonstrated that administration of GW0742, a specific PPARδ ligand, provided beneficial effects to rats subjected to cecal ligation and puncture, as shown by reduced systemic release of pro-inflammatory cytokines and neutrophil infiltration in lung, liver, and cecum, when compared with vehicle treatment. Molecular analysis revealed that treatment with GW0742 reduced NF-κB binding to DNA in lung and liver. In parallel experiments, heterozygous PPARδ-deficient mice suffered exaggerated lethality when subjected to cecal ligation and puncture and exhibited severe lung injury and higher levels of circulating tumor necrosis factor-α (TNFα) and keratinocyte-derived chemokine than wild-type mice. Furthermore, in lipopolysaccharide-stimulated J774.A1 macrophages, GW0742 reduced TNFα production by inhibiting NF-κB activation. RNA silencing of PPARδ abrogated the inhibitory effects of GW0742 on TNFα production. Chromatin immunoprecipitation assays revealed that PPARδ displaced the NF-κB p65 subunit from the κB elements of the TNFα promoter, while recruiting the co-repressor BCL6. These data suggest that PPARδ is a crucial anti-inflammatory regulator, providing a basis for novel sepsis therapies.

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Available from: James A Cook, Oct 13, 2015
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    • "We thus pointed to PPARδ down-regulation to validate our approach, with the aim of understanding if PPARδ suppression is confirmed also in HCC, and if it could negatively modulate hepatoma cells growth. PPARδ is a promising target since is a major player in the control of metabolic pathways modulating LR (glucose and fatty acid metabolism) [79], exerts an anti-inflammatory activity [80], have been involved in the modulation of cell proliferation and carcinogenesis [19], and can be modulated pharmacologically. The contribution of PPARδ in hepatocyte proliferation and HCC is strongly discussed in the literature; PPARδ knock out animals are characterized by delayed LR exclusively in the early phases of LR, but no data are available for time points later than three days (when PPARδ KO liver weight/body weight ratio are comparable to wild type mice) [36]. "
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    ABSTRACT: Background & Aims Liver regeneration (LR) is a valuable model for studying mechanisms modulating hepatocyte proliferation. Nuclear receptors (NRs) are key players in the control of cellular functions, being ideal modulators of hepatic proliferation and carcinogenesis. Methods & Results We used a previously validated RT-qPCR platform to profile modifications in the expression of all 49 members of the NR superfamily in mouse liver during LR. Twenty-nine NR transcripts were significantly modified in their expression during LR, including fatty acid (peroxisome proliferator-activated receptors, PPARs) and oxysterol (liver X receptors, Lxrs) sensors, circadian masters RevErbα and RevErbβ, glucocorticoid receptor (Gr) and constitutive androxane receptor (Car). In order to detect the NRs that better characterize proliferative status vs. proliferating liver, we used the novel Random Forest (RF) analysis to selected a trio of down-regulated NRs (thyroid receptor alpha, Trα; farsenoid X receptor beta, Fxrβ; Pparδ) as best discriminators of the proliferating status. To validate our approach, we further studied PPARδ role in modulating hepatic proliferation. We first confirmed the suppression of PPARδ both in LR and human hepatocellular carcinoma at protein level, and then demonstrated that PPARδ agonist GW501516 reduces the proliferative potential of hepatoma cells. Conclusions Our data suggest that NR transcriptome is modulated in proliferating liver and is a source of biomarkers and bona fide pharmacological targets for the management of liver disease affecting hepatocyte proliferation.
    PLoS ONE 08/2014; 9(8):e104449. DOI:10.1371/journal.pone.0104449 · 3.23 Impact Factor
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    • "These results corroborate human studies indicating that apoptotic factors may be early biomarkers of sepsis that modulate lymphocyte and monocyte activity [23,36]. In the lungs, we observed minimal extravasation of red cells,but little accumulation of inflammatory cells into the air spaces as described by Zingarelli et al.[37]. "
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    ABSTRACT: The lack of a reliable scoring system that predicts the development of septic shock and death precludes comparison of disease and/or treatment outcomes in animal models of sepsis. We developed a murine sepsis score (MSS) that evaluates seven clinical variables, and sought to assess its validity and reliability in an experimental mouse model of polymicrobial sepsis. Stool collected from the cecum of C57BL/6 (B6) mice was dissolved in 0.9 % normal saline (NS) and filtered, resulting in a fecal solution (FS) which was injected intraperitoneally into B6 mice. Disease severity was monitored by MSS during the experimental timeline. Blood and tissue samples were harvested for the evaluation of inflammatory changes after sepsis induction. The correlation between pro-inflammatory markers and MSS was assessed by the Spearman rank correlation coefficient. Mice injected with FS at a concentration of 90 mg/mL developed polymicrobial sepsis with a 75 % mortality rate at 24 hours. The MSS was highly predictive of sepsis progression and mortality, with excellent discriminatory power, high internal consistency (Cronbach alpha coefficient = 0.92), and excellent inter-rater reliability (intra-class coefficient = 0.96). An MSS of 3 had a specificity of 100 % for predicting onset of septic shock and death within 24 hours. Hepatic dysfunction and systemic pro-inflammatory responses were confirmed by biochemical and cytokine analyses where the latter correlated well with the MSS. Significant bacterial dissemination was noted in multiple organs. Furthermore, the liver, spleen, and intestine demonstrated histopathological evidence of injury. The MSS reliably predicts disease progression and mortality in an animal model of polymicrobial sepsis. More importantly, it may be used to assess and compare outcomes among various experimental models of sepsis, and serve as an ethically acceptable alternative to death as an endpoint.
    BMC Research Notes 04/2014; 7(1):233. DOI:10.1186/1756-0500-7-233
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    • "Unlike PPARα and PPARγ, the role of PPARβ in liver regeneration has not been studied. In addition to regulating glucose and lipid metabolism, PPARβ displays an anti-inflammatory activity, which could be important in the modulation of liver regeneration [14]. Ligand activation of PPARβ protects against CCl4-induced hepatotoxicity by repression of pro-inflammatory genes [15]. "
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    ABSTRACT: The current study tests the hypothesis that peroxisome proliferator-activated receptor β (PPARβ) has a role in liver regeneration due to its effect in regulating energy homeostasis and cell proliferation. The role of PPARβ in liver regeneration was studied using two-third partial hepatectomy (PH) in Wild-type (WT) and PPARβ-null (KO) mice. In KO mice, liver regeneration was delayed and the number of Ki-67 positive cells reached the peak at 60 hr rather than at 36-48 hr after PH shown in WT mice. RNA-sequencing uncovered 1344 transcriptomes that were differentially expressed in regenerating WT and KO livers. About 70% of those differentially expressed genes involved in glycolysis and fatty acid synthesis pathways failed to induce during liver regeneration due to PPARβ deficiency. The delayed liver regeneration in KO mice was accompanied by lack of activation of phosphoinositide-dependent kinase 1 (PDK1)/Akt. In addition, cell proliferation-associated increase of genes encoding E2f transcription factor (E2f) 1-2 and E2f7-8 as well as their downstream target genes were not noted in KO livers 36-48 hr after PH. E2fs have dual roles in regulating metabolism and proliferation. Moreover, transient steatosis was only found in WT, but not in KO mice 36 hr after PH. These data suggested that PPARβ-regulated PDK1/Akt and E2f signaling that controls metabolism and proliferation is involved in the normal progression of liver regeneration.
    PLoS ONE 06/2013; 8(6):e65644. DOI:10.1371/journal.pone.0065644 · 3.23 Impact Factor
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