Fatty acid-binding protein 5 limits the anti-inflammatory response in murine macrophages

Moore, Sherri M.; Holt, Vivian V.; Malpass, Lillie R.; Hines, Ian N.; Wheeler, Michael D.

doi:10.1016/j.molimm.2015.06.001

Cited by 58 publications

(48 citation statements)

References 27 publications

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“…Overexpression of FABP5 in adipose tissue results in increased lipolysis, decreased fat mass, and potentiated insulin resistance (Hertzel et al, 2006). In the liver, FABP5 displays an anti-inflammatory action by regulating macrophage phenotypes (Moore et al, 2015). Consistent with a report showing that FABP5 is negatively regulated by Nrf2 in normal and fatty livers (Chartoumpekis et al, 2013), we additionally revealed that hepatic FABP5 positively responds to estrogen signaling in NAFLD.…”

Section: Crosstalk Of Nrf2 and Estrogen Signaling In Lipid Metabolismsupporting

confidence: 88%

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen

Wei

Zou

Lee

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates multiple biologic processes, including hepatic lipid metabolism. Estrogen exerts actions affecting energy homeostasis, including a liver fat-lowering effect. Increasing evidence indicates the crosstalk between these two molecules. The aim of this study was to evaluate whether Nrf2 modulates estrogen signaling in hepatic lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) was induced in wild-type and Nrf2-null mice fed a high-fat diet and the liver fat-lowering effect of exogenous estrogen was subsequently assessed. We found that exogenous estrogen eliminated 49% and 90% of hepatic triglycerides in wild-type and Nrf2-null mice with NAFLD, respectively. This observation demonstrates that Nrf2 signaling is antagonistic to estrogen signaling in hepatic fat metabolism; thus, Nrf2 absence results in striking amplification of the liver fat-lowering effect of estrogen. In addition, we found the association of trefoil factor 3 and fatty acid binding protein 5 with the liver fat-lowering effect of estrogen. In summary, we identified Nrf2 as a novel and potent inhibitor of estrogen signaling in hepatic lipid metabolism. Our finding may provide a potential strategy to treat NAFLD by dually targeting Nrf2 and estrogen signaling.

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Section: Crosstalk Of Nrf2 and Estrogen Signaling In Lipid Metabolismsupporting

confidence: 88%

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen

Wei

Zou

Lee

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…Many of them are associated with various MG responses. For example, MRC2, Axl, SPP1, Clec7a, Pdcd1, Lgals3, and Fabp5 are known to push macrophages into M2 phenotype (Burke, Kerr, Moriarty, Finn, & Roche, ; Jiao, Natoli, Valter, Provis, & Rutar, ; Moore, Holt, Malpass, Hines, & Wheeler, ; Petruzzi, Cherubini, Salum, & de Figueiredo, ; Rahimian, Beland, & Kriz, ; Yao et al, ; Zhang, Du, Chen, & Xiang, ). The M2 anti‐inflammatory mode is known to be protective for neurogenesis (Yuan et al, ).…”

Section: Resultsmentioning

confidence: 99%

Unique role for dentate gyrus microglia in neuroblast survival and in VEGF‐induced activation

Kreisel

Wolf

Keshet

et al. 2018

Glia

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Neurogenic roles of microglia (MG) are thought to include an active role in adult hippocampal neurogenesis in addition to their established roles in pruning surplus dendrites and clearing dead neuroblasts. However, identification of such a role and its delineation in the neurogenic cascade is yet to be established. Using diphtheria toxin‐aided MG ablation, we show that MG reduction in the DG—the site where neuronal stem cells (NSCs) reside—is sufficient to impede overall hippocampal neurogenesis due to reduced survival of newly formed neuroblasts. To examine whether MG residing in the hippocampal neurogenic zone are inherently different from MG residing elsewhere in the hippocampus, we compared growth factor responsiveness of DG MG with that of CA1 MG. Strikingly, transgenic induction of the potent neurogenic factor VEGF elicited robust on‐site MG expansion and activation exclusively in the DG and despite eliciting a comparable angiogenic response in the CA1 and elsewhere. Temporally, DG‐specific MG expansion preceded both angiogenic and neurogenic responses. Remarkably, even partial MG reduction during the process of VEGF‐induced neurogenesis led to reducing the number of newly formed neuroblasts to the basal level. Transcriptomic analysis of MG retrieved from the naïve DG and CA1 uncovered a set of genes preferentially expressed in DG MG. Notably the tyrosine kinase Axl is exclusively expressed in naïve and VEGF‐induced DG MG and its inhibition prevented neurogenesis augmentation by VEGF. Taken together, findings uncover inherent unique properties of DG MG of supporting both basal‐ and VEGF‐induced adult hippocampal neurogenesis.

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“…Altered lipid homeostasis can have a profound effect on macrophage function, promoting inflammatory cytokine production. Loss of fatty acid binding protein 5 (FABP5) promotes LPS-induced IL12 production in vitro and in vivo from hepatic macrophages further supporting an interaction among lipid, macrophages, and their production of IL12 [ 3 ]. The link between IL12 and PPARα at the level of the macrophage remains unclear but is likely related to lipid accumulation and subsequent inflammatory transcription factor activation.…”

Section: Discussionmentioning

confidence: 99%

Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice

et al. 2018

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BackgroundPeroxisome proliferator activated receptor alpha (PPARα), a regulator of enzymes involved in β oxidation, has been reported to influence lymphocyte activation. The purpose of this study was to determine whether PPARα plays a role in T cell-mediated hepatitis induced by Concanavalin A (ConA).MethodsWild type (wt) or PPARα-deficient (PPARα−/−) mice were treated with ConA (15 mg/kg) by intravenous injection 0, 10 or 24 h prior to sacrifice and serum and tissue collection for analysis of tissue injury, cytokine response, T cell activation and characterization.ResultsTen and 24 h following ConA administration, wt mice had significant liver injury as demonstrated by serum transaminase levels, inflammatory cell infiltrate, hepatocyte apoptosis, and expression of several cytokines including interleukin 4 (IL4) and interferon gamma (IFNγ). In contrast, PPARα−/− mice were protected from ConA-induced liver injury with significant reductions in serum enzyme release, greatly reduced inflammatory cell infiltrate, hepatocellular apoptosis, and IFNγ expression, despite having similar levels of hepatic T cell activation and IL4 expression. This resistance to liver injury was correlated with reduced numbers of hepatic natural killer T (NKT) cells and their in vivo responsiveness to alpha-galactosylceramide. Interestingly, adoptive transfer of either wt or PPARα−/− splenocytes reconstituted ConA liver injury and cytokine production in lymphocyte-deficient, severe combined immunodeficient mice implicating PPARα within the liver, possibly through support of IL15 expression and/or suppression of IL12 production and not the lymphocyte as the key regulator of T cell activity and ConA-induced liver injury.ConclusionTaken together, these data suggest that PPARα within the liver plays an important role in ConA-mediated liver injury through regulation of NKT cell recruitment and/or survival.

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Fatty acid-binding protein 5 limits the anti-inflammatory response in murine macrophages

Cited by 58 publications

References 27 publications

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen

Unique role for dentate gyrus microglia in neuroblast survival and in VEGF‐induced activation

Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice

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