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Leukotriene B4 Is a Physiologically Relevant Endogenous Peroxisome Proliferator-activated Receptor-α Agonist
Open accessAbstract
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.
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“the PPARα nuclear receptor was of prime interest because is an established modulator of lipid metabolism”
From Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy (2019) · cites this paper as [54]
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Metadata
- Authors
- Narala, V. R., Adapala, R. K., Suresh, M. V., Brock, T. G., Peters-Golden, M., & Reddy, R. C.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Reddy, Raju C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-07
- Volume
- 285
- Issue
- 29
- Pages
- 22067-22074
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2903376
- OpenAlex
- W2086928559
- Cited by
- 126
- References
- 29
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 5 · 2023: 10 · 2022: 4 · 2021: 7 · 2020: 7 · 2019: 7 · 2018: 5 · 2017: 7 · 2016: 8 · 2015: 8 · 2014: 4 · 2013: 13 · 2012: 12
- FWCI
- 5.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL-093196, R01HL093196)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- leukotriene B4, PPARα, 5-lipoxygenase, leukotriene A4, inflammation, eicosanoids, nuclear receptor signaling, immune cells
- MeSH terms
- Amino Acids, Animals, Arachidonate 5-Lipoxygenase, Cell Line, Humans, Leukotriene B4, Ligands, Models, Molecular, Computational Biology, PPAR alpha, Mice
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