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Leukotriene B4 is a physiologically relevant endogenous peroxisome proliferator-activated receptor-alpha agonist.

ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that play central roles in metabolism and inflammation. Although a variety of compounds have been shown to activate PPARs, identification of physiologically relevant ligands has proven difficult. In silico studies of lipid derivatives reported here identify specific 5-lipoxygenase products as candidate physiologically relevant PPAR-alpha activators. Subsequent studies show both in vitro and in a murine model of inflammation that 5-lipoxygenase stimulation induces PPAR-alpha signaling and that this results specifically from production of the inflammatory mediator and chemoattractant leukotriene B(4) (LTB(4)). Activation of PPAR-alpha is a direct effect of intracellularly generated LTB(4) binding to the nuclear receptor and not of secreted LTB(4) acting via its cell-surface receptors. Activation of PPAR-alpha reduces secretion of LTB(4) by stimulating degradation of this fatty acid derivative. We also show that the LTB(4) precursors leukotriene A(4) (LTA(4)) and 5-hydroperoxyeicosatetrenoic acid (5-HPETE) activate PPAR-alpha but have no significant endogenous effect independent of conversion to LTB(4). We conclude that LTB(4) is a physiologically relevant PPAR-alpha activator in cells of the immune system. This, together with previous findings, demonstrates that different types of lipids serve as endogenous PPAR-alpha ligands, with the relevant ligand varying between functionally different cell types. Our results also support the suggestion that regulation of inflammation may involve balancing proinflammatory effects of LTB(4), exerted through cell-surface receptors, and anti-inflammatory effects exerted through PPAR-alpha activation.

SUBMITTER: Narala VR

PROVIDER: S-EPMC2903376 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Leukotriene B4 is a physiologically relevant endogenous peroxisome proliferator-activated receptor-alpha agonist.

Narala Venkata R VR Adapala Ravi K RK Suresh Madathilparambil V MV Brock Thomas G TG Peters-Golden Marc M Reddy Raju C RC

The Journal of biological chemistry 20100416 29

Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that play central roles in metabolism and inflammation. Although a variety of compounds have been shown to activate PPARs, identification of physiologically relevant ligands has proven difficult. In silico studies of lipid derivatives reported here identify specific 5-lipoxygenase products as candidate physiologically relevant PPAR-alpha activators. Subsequent studies show both in vitro and in a murine model of ...[more]

PMID: 20400503

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Project description:Our aim was to investigate if the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone modulates inflammation through PPARalpha mechanisms.The thiazolidinediones (TZDs) pioglitazone and rosiglitazone are insulin-sensitizing PPARgamma agonists used to treat type 2 diabetes (T2DM). Despite evidence for TZDs limiting inflammation and atherosclerosis, questions exist regarding differential responses to TZDs. In a double-blinded, placebo-controlled 16-week trial among recently diagnosed T2DM subjects (n = 34), pioglitazone-treated subjects manifested lower triglycerides and lacked the increase in soluble vascular cell adhesion molecules (sVCAM)-1 evident in the placebo group. Previously we reported PPARalpha but not PPARgamma agonists could repress VCAM-1 expression. Since both triglyceride-lowering and VCAM-1 repression characterize PPARalpha activation, we studied pioglitazone's effects via PPARalpha.Pioglitazone effects on known PPARalpha responses--ligand binding domain activation and PPARalpha target gene expression--were tested in vitro and in vivo, including in wild-type and PPARalpha-deficient cells and mice, and compared with the effects of other PPARgamma (rosiglitazone) and PPARalpha (WY14643) agonists.Pioglitazone repressed endothelial TNFalpha-induced VCAM-1 messenger ribonucleic acid expression and promoter activity, and induced hepatic IkappaBalpha in a manner dependent on both pioglitazone exposure and PPARalpha expression. Pioglitazone also activated the PPARalpha ligand binding domain and induced PPARalpha target gene expression, with in vitro effects that were most pronounced in endothelial cells. In vivo, pioglitazone administration modulated sVCAM-1 levels and IkappaBalpha expression in wild-type but not PPARalpha-deficient mice.Pioglitazone regulates inflammatory target genes in hepatic (IkappaBalpha) and endothelial (VCAM-1) settings in a PPARalpha-dependent manner. These data offer novel mechanisms that may underlie distinct TZD responses.

Dataset Information

Leukotriene B4 is a physiologically relevant endogenous peroxisome proliferator-activated receptor-alpha agonist.

Publications

Leukotriene B4 is a physiologically relevant endogenous peroxisome proliferator-activated receptor-alpha agonist.

Similar Datasets

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