A FABP4-PPARγ signaling axis regulates human monocyte responses to electrophilic fatty acid nitroalkenes
Nitro-fatty acids (NO2-FA) are electrophilic lipid mediators derived from unsaturated fatty acid nitration. These species are produced endogenously by metabolic and inflammatory reactions and mediate anti-oxidative and anti-inflammatory responses. NO2-FA have been postulated as partial agonists of t...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-01-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231719308523 |
| _version_ | 1828396993807908864 |
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| author | M. Lamas Bervejillo J. Bonanata G.R. Franchini A. Richeri J.M. Marqués B.A. Freeman F.J. Schopfer E.L. Coitiño B. Córsico H. Rubbo A.M. Ferreira |
| author_facet | M. Lamas Bervejillo J. Bonanata G.R. Franchini A. Richeri J.M. Marqués B.A. Freeman F.J. Schopfer E.L. Coitiño B. Córsico H. Rubbo A.M. Ferreira |
| author_sort | M. Lamas Bervejillo |
| collection | DOAJ |
| description | Nitro-fatty acids (NO2-FA) are electrophilic lipid mediators derived from unsaturated fatty acid nitration. These species are produced endogenously by metabolic and inflammatory reactions and mediate anti-oxidative and anti-inflammatory responses. NO2-FA have been postulated as partial agonists of the Peroxisome Proliferator-Activated Receptor gamma (PPARγ), which is predominantly expressed in adipocytes and myeloid cells. Herein, we explored molecular and cellular events associated with PPARγ activation by NO2-FA in monocytes and macrophages. NO2-FA induced the expression of two PPARγ reporter genes, Fatty Acid Binding Protein 4 (FABP4) and the scavenger receptor CD36, at early stages of monocyte differentiation into macrophages. These responses were inhibited by the specific PPARγ inhibitor GW9662. Attenuated NO2-FA effects on PPARγ signaling were observed once cells were differentiated into macrophages, with a significant but lower FABP4 upregulation, and no induction of CD36. Using in vitro and in silico approaches, we demonstrated that NO2-FA bind to FABP4. Furthermore, the inhibition of monocyte FA binding by FABP4 diminished NO2-FA-induced upregulation of reporter genes that are transcriptionally regulated by PPARγ, Keap1/Nrf2 and HSF1, indicating that FABP4 inhibition mitigates NO2-FA signaling actions. Overall, our results affirm that NO2-FA activate PPARγ in monocytes and upregulate FABP4 expression, thus promoting a positive amplification loop for the downstream signaling actions of this mediator. Keywords: Nitro-fatty acids, Peroxisome proliferator-activated receptor gamma, Fatty acid binding protein 4, Monocytes, Macrophages, Lipid signaling |
| first_indexed | 2024-12-10T08:38:58Z |
| format | Article |
| id | doaj.art-1644e9c7975b4ddf814cc73414658327 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-10T08:38:58Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-1644e9c7975b4ddf814cc734146583272022-12-22T01:55:53ZengElsevierRedox Biology2213-23172020-01-0129A FABP4-PPARγ signaling axis regulates human monocyte responses to electrophilic fatty acid nitroalkenesM. Lamas Bervejillo0J. Bonanata1G.R. Franchini2A. Richeri3J.M. Marqués4B.A. Freeman5F.J. Schopfer6E.L. Coitiño7B. Córsico8H. Rubbo9A.M. Ferreira10Laboratorio de Inmunología, Instituto de Higiene, Facultad de Ciencias/Facultad de Química, Universidad de la República (UdelaR), Montevideo, CP 11600, UruguayLaboratorio de Química Teórica y Computacional, Instituto de Química Biológica, Facultad de Ciencias, UdelaR, Montevideo, CP 11400, Uruguay; Centro de Investigaciones Biomédicas (CeInBio), UdelaR, Montevideo, CP 11800, UruguayInstituto de Investigaciones Bioquímicas de La Plata (INIBIOLP), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, ArgentinaLaboratorio de Biología Celular, Departamento de Neurofarmacología Experimental, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, CP 11600, UruguayLaboratorio de Investigación en Vacunas, Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, UdelaR, Montevideo, CP 11600, UruguayDepartment of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USADepartment of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USALaboratorio de Química Teórica y Computacional, Instituto de Química Biológica, Facultad de Ciencias, UdelaR, Montevideo, CP 11400, Uruguay; Centro de Investigaciones Biomédicas (CeInBio), UdelaR, Montevideo, CP 11800, Uruguay; Corresponding author. Laboratorio de Química Teórica y Computacional, Instituto de Química Biológica, Facultad de Ciencias, UdelaR, Montevideo, CP 11400, Uruguay.Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, ArgentinaCentro de Investigaciones Biomédicas (CeInBio), UdelaR, Montevideo, CP 11800, Uruguay; Departamento de Bioquímica, Facultad de Medicina, UdelaR, Montevideo, CP 11800, UruguayLaboratorio de Inmunología, Instituto de Higiene, Facultad de Ciencias/Facultad de Química, Universidad de la República (UdelaR), Montevideo, CP 11600, Uruguay; Corresponding author. Laboratorio de Inmunología, Instituto de Higiene, Facultad de Ciencias/Facultad de Química, Universidad de la República (UdelaR), Montevideo, CP 11600, Uruguay.Nitro-fatty acids (NO2-FA) are electrophilic lipid mediators derived from unsaturated fatty acid nitration. These species are produced endogenously by metabolic and inflammatory reactions and mediate anti-oxidative and anti-inflammatory responses. NO2-FA have been postulated as partial agonists of the Peroxisome Proliferator-Activated Receptor gamma (PPARγ), which is predominantly expressed in adipocytes and myeloid cells. Herein, we explored molecular and cellular events associated with PPARγ activation by NO2-FA in monocytes and macrophages. NO2-FA induced the expression of two PPARγ reporter genes, Fatty Acid Binding Protein 4 (FABP4) and the scavenger receptor CD36, at early stages of monocyte differentiation into macrophages. These responses were inhibited by the specific PPARγ inhibitor GW9662. Attenuated NO2-FA effects on PPARγ signaling were observed once cells were differentiated into macrophages, with a significant but lower FABP4 upregulation, and no induction of CD36. Using in vitro and in silico approaches, we demonstrated that NO2-FA bind to FABP4. Furthermore, the inhibition of monocyte FA binding by FABP4 diminished NO2-FA-induced upregulation of reporter genes that are transcriptionally regulated by PPARγ, Keap1/Nrf2 and HSF1, indicating that FABP4 inhibition mitigates NO2-FA signaling actions. Overall, our results affirm that NO2-FA activate PPARγ in monocytes and upregulate FABP4 expression, thus promoting a positive amplification loop for the downstream signaling actions of this mediator. Keywords: Nitro-fatty acids, Peroxisome proliferator-activated receptor gamma, Fatty acid binding protein 4, Monocytes, Macrophages, Lipid signalinghttp://www.sciencedirect.com/science/article/pii/S2213231719308523 |
| spellingShingle | M. Lamas Bervejillo J. Bonanata G.R. Franchini A. Richeri J.M. Marqués B.A. Freeman F.J. Schopfer E.L. Coitiño B. Córsico H. Rubbo A.M. Ferreira A FABP4-PPARγ signaling axis regulates human monocyte responses to electrophilic fatty acid nitroalkenes Redox Biology |
| title | A FABP4-PPARγ signaling axis regulates human monocyte responses to electrophilic fatty acid nitroalkenes |
| title_full | A FABP4-PPARγ signaling axis regulates human monocyte responses to electrophilic fatty acid nitroalkenes |
| title_fullStr | A FABP4-PPARγ signaling axis regulates human monocyte responses to electrophilic fatty acid nitroalkenes |
| title_full_unstemmed | A FABP4-PPARγ signaling axis regulates human monocyte responses to electrophilic fatty acid nitroalkenes |
| title_short | A FABP4-PPARγ signaling axis regulates human monocyte responses to electrophilic fatty acid nitroalkenes |
| title_sort | fabp4 pparγ signaling axis regulates human monocyte responses to electrophilic fatty acid nitroalkenes |
| url | http://www.sciencedirect.com/science/article/pii/S2213231719308523 |
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