Structural basis for the activation of PPARγ by oxidized fatty acids

Itoh, Toshimasa; Fairall, Louise; Amin, Kush; Inaba, Yuka; Szántó, Attila; Bálint, Bálint László; Nagy, László; Yamamoto, Keiko; Schwabe, John W. R.

doi:10.1038/nsmb.1474

Cited by 410 publications

(392 citation statements)

References 39 publications

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“…Our results indicating that COX-2 is up-regulated and PPARγ is down-regulated, in FABP7-positive U87 cells cultured in an AA-rich environment, are in keeping with COX-2 being down-regulated by PPARγ in DHA-treated malignant glioma [18]. It is worth mentioning that some DHA metabolites such as 17-hydroxy DHA are more potent activators of PPARγ than DHA itself [112,114] and therefore could contribute to the DHA effect.…”

Section: Docosahexaenoic Acid-related Mechanismssupporting

confidence: 71%

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Interaction of brain fatty acid-binding protein with the polyunsaturated fatty acid environment as a potential determinant of poor prognosis in malignant glioma

Elsherbiny

Emara

Godbout

2013

Progress in Lipid Research

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Malignant gliomas are the most common adult brain cancers. In spite of aggressive treatment, recurrence occurs in the great majority of patients and is invariably fatal. Polyunsaturated fatty acids are abundant in brain, particularly ω-6 arachidonic acid (AA) and ω-3 docosahexaenoic acid (DHA). Although the levels of ω-6 and ω-3 polyunsaturated fatty acids are tightly regulated in brain, the ω-6:ω-3 ratio is dramatically increased in malignant glioma, suggesting deregulation of fundamental lipid homeostasis in brain tumor tissue. The migratory properties of malignant glioma cells can be modified by altering the ratio of AA:DHA in growth medium, with increased migration observed in AA-rich medium. This fatty acid-dependent effect on cell migration is dependent on expression of the brain fatty acid binding protein (FABP7) previously shown to bind DHA and AA. Increased levels of enzymes involved in eicosanoid production in FABP7-positive malignant glioma cells suggest that FABP7 is an important modulator of AA metabolism. We provide evidence that increased production of eicosanoids in FABP7-positive malignant glioma growing in an AA-rich environment contributes to tumor infiltration in the brain. We discuss pathways and molecules that may underlie FABP7/AA-mediated promotion of cell migration and FABP7/DHA-mediated inhibition of cell migration in malignant glioma.

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Section: Docosahexaenoic Acid-related Mechanismssupporting

confidence: 71%

“…Our laboratory has shown that the inhibitory effect of DHA on cell migration is partially mediated by PPARγ [18]. A documented natural ligand for PPARγ is DHA [112]. Furthermore, FABP7/DHA-dependent inhibition of migration is dependent on the nuclear localization of FABP7 [18].…”

Section: Docosahexaenoic Acid-related Mechanismsmentioning

confidence: 99%

Interaction of brain fatty acid-binding protein with the polyunsaturated fatty acid environment as a potential determinant of poor prognosis in malignant glioma

Elsherbiny

Emara

Godbout

2013

Progress in Lipid Research

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“…Indeed, nuclear receptors belonging to the PPAR family have emerged as relevant in anti-inflammatory signaling mechanisms and may bind lipids (16). For example, oxidized fatty acids at concentrations in the micromolar range can activate PPARγ, which possesses an unusually large ligand-binding cavity that accommodates a wide range of molecules rather than a single ligand (21). Because RvD1 did not activate PPAR signaling within its bioactive concentration range, it was reasonable to determine whether the recognition sites were present on the surfaces of phagocytes, which was in line with the finding that RvD1 actions were PTX sensitive, pointing to the family of GPCRs.…”

Section: Discussionmentioning

confidence: 99%

Resolvin D1 binds human phagocytes with evidence for proresolving receptors

Krishnamoorthy

Recchiuti

Chiang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

636

710

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Endogenous mechanisms that act in the resolution of acute inflammation are essential for host defense and the return to homeostasis. Resolvin D1 (RvD1), biosynthesized during resolution, displays potent and stereoselective anti-inflammatory actions, such as limiting neutrophil infiltration and proresolving actions. Here, we demonstrate that RvD1 actions on human polymorphonuclear leukocytes (PMNs) are pertussis toxin sensitive, decrease actin polymerization, and block LTB 4 -regulated adhesion molecules (β2 integrins). Synthetic [ 3 H]-RvD1 was prepared, which revealed specific RvD1 recognition sites on human leukocytes. Screening systems to identify receptors for RvD1 gave two candidates-ALX, a lipoxin A 4 receptor, and GPR32, an orphan -that were confirmed using a β-arrestin-based ligand receptor system. Nuclear receptors including retinoid X receptor-α and peroxisome proliferator-activated receptor-α, -δ, -γ were not activated by either resolvin E1 or RvD1 at bioactive nanomolar concentrations. RvD1 enhanced macrophage phagocytosis of zymosan and apoptotic PMNs, which increased with overexpression of human ALX and GPR32 and decreased with selective knockdown of these G-protein-coupled receptors. Also, ALX and GPR32 surface expression in human monocytes was up-regulated by zymosan and granulocyte-monocyte-colony-stimulating factor. These results indicate that RvD1 specifically interacts with both ALX and GPR32 on phagocytes and suggest that each plays a role in resolving acute inflammation.inflammation | leukocytes | lipid mediators | resolution | polyunsaturated fatty acids

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“…Studies have identified many ligands that activate and modulate PPAR functions (Berger et al, 1999;Forman et al, 1995;Itoh et al, 2008;Kliewer et al, 1997;Sanderson et al, 2009;Varga et al, 2011). These ligands are summarized in Table 1.…”

Section: Ppar Ligandsmentioning

confidence: 99%

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

Choi¹,

Bothwell

2012

Molecules and Cells

149

111

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Members of the nuclear receptor superfamily function as transcription factors involved in innate and adaptive immunity as well as lipid metabolism. These highly conserved proteins participate in ligand-dependent or -independent regulatory mechanisms that affect gene expression. Peroxisome proliferator-activated receptors (PPARs), which include PPARα, PPARβ/δ, and PPARγ, are a group of nuclear receptor proteins that play diverse roles in cellular differentiation, development, and metabolism. Each PPAR subfamily is activated by different endogenous and synthetic ligands. Recent studies using specific ligand treatments and cell type-specific PPAR knockout mice have revealed important roles for these proteins in T-cell-related autoimmune diseases. Moreover, PPARs have been shown to regulate T-cell survival, activation, and CD4 + T helper cell differentiation into the Th1, Th2, Th17, and Treg lineages. Here, we review the studies that provide insight into the important regulatory roles of PPARs in T-cell activation, survival, proliferation, differentiation, and autoimmune disease.

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Structural basis for the activation of PPARγ by oxidized fatty acids

Cited by 410 publications

References 39 publications

Interaction of brain fatty acid-binding protein with the polyunsaturated fatty acid environment as a potential determinant of poor prognosis in malignant glioma

Interaction of brain fatty acid-binding protein with the polyunsaturated fatty acid environment as a potential determinant of poor prognosis in malignant glioma

Resolvin D1 binds human phagocytes with evidence for proresolving receptors

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

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