PPAR-γ Agonist GW1929 Targeted to Macrophages with Dendrimer–Graphene Nanostars Reduces Liver Fibrosis and Inflammation
Macrophages play essential roles during the progression of chronic liver disease. They actively participate in the response to liver damage and in the balance between fibrogenesis and regression. The activation of the PPARγ nuclear receptor in macrophages has traditionally been associated with an an...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-05-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/5/1452 |
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| author | Alazne Moreno-Lanceta Mireia Medrano-Bosch Blanca Simón-Codina Montserrat Barber-González Wladimiro Jiménez Pedro Melgar-Lesmes |
| author_facet | Alazne Moreno-Lanceta Mireia Medrano-Bosch Blanca Simón-Codina Montserrat Barber-González Wladimiro Jiménez Pedro Melgar-Lesmes |
| author_sort | Alazne Moreno-Lanceta |
| collection | DOAJ |
| description | Macrophages play essential roles during the progression of chronic liver disease. They actively participate in the response to liver damage and in the balance between fibrogenesis and regression. The activation of the PPARγ nuclear receptor in macrophages has traditionally been associated with an anti-inflammatory phenotype. However, there are no PPARγ agonists with high selectivity for macrophages, and the use of full agonists is generally discouraged due to severe side effects. We designed dendrimer–graphene nanostars linked to a low dose of the GW1929 PPARγ agonist (DGNS-GW) for the selective activation of PPARγ in macrophages in fibrotic livers. DGNS-GW preferentially accumulated in inflammatory macrophages in vitro and attenuated macrophage pro-inflammatory phenotype. The treatment with DGNS-GW in fibrotic mice efficiently activated liver PPARγ signaling and promoted a macrophage switch from pro-inflammatory M1 to anti-inflammatory M2 phenotype. The reduction of hepatic inflammation was associated with a significant reduction in hepatic fibrosis but did not alter liver function or hepatic stellate cell activation. The therapeutic antifibrotic utility of DGNS-GW was attributed to an increased expression of hepatic metalloproteinases that allowed extracellular matrix remodeling. In conclusion, the selective activation of PPARγ in hepatic macrophages with DGNS-GW significantly reduced hepatic inflammation and stimulated extracellular matrix remodeling in experimental liver fibrosis. |
| first_indexed | 2024-03-11T03:24:53Z |
| format | Article |
| id | doaj.art-edd95e9aa11840528f6c104c74d88471 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T03:24:53Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-edd95e9aa11840528f6c104c74d884712023-11-18T02:51:48ZengMDPI AGPharmaceutics1999-49232023-05-01155145210.3390/pharmaceutics15051452PPAR-γ Agonist GW1929 Targeted to Macrophages with Dendrimer–Graphene Nanostars Reduces Liver Fibrosis and InflammationAlazne Moreno-Lanceta0Mireia Medrano-Bosch1Blanca Simón-Codina2Montserrat Barber-González3Wladimiro Jiménez4Pedro Melgar-Lesmes5Department of Biomedicine, School of Medicine, University of Barcelona, 08036 Barcelona, SpainDepartment of Biomedicine, School of Medicine, University of Barcelona, 08036 Barcelona, SpainDepartment of Biomedicine, School of Medicine, University of Barcelona, 08036 Barcelona, SpainDepartment of Biomedicine, School of Medicine, University of Barcelona, 08036 Barcelona, SpainDepartment of Biomedicine, School of Medicine, University of Barcelona, 08036 Barcelona, SpainDepartment of Biomedicine, School of Medicine, University of Barcelona, 08036 Barcelona, SpainMacrophages play essential roles during the progression of chronic liver disease. They actively participate in the response to liver damage and in the balance between fibrogenesis and regression. The activation of the PPARγ nuclear receptor in macrophages has traditionally been associated with an anti-inflammatory phenotype. However, there are no PPARγ agonists with high selectivity for macrophages, and the use of full agonists is generally discouraged due to severe side effects. We designed dendrimer–graphene nanostars linked to a low dose of the GW1929 PPARγ agonist (DGNS-GW) for the selective activation of PPARγ in macrophages in fibrotic livers. DGNS-GW preferentially accumulated in inflammatory macrophages in vitro and attenuated macrophage pro-inflammatory phenotype. The treatment with DGNS-GW in fibrotic mice efficiently activated liver PPARγ signaling and promoted a macrophage switch from pro-inflammatory M1 to anti-inflammatory M2 phenotype. The reduction of hepatic inflammation was associated with a significant reduction in hepatic fibrosis but did not alter liver function or hepatic stellate cell activation. The therapeutic antifibrotic utility of DGNS-GW was attributed to an increased expression of hepatic metalloproteinases that allowed extracellular matrix remodeling. In conclusion, the selective activation of PPARγ in hepatic macrophages with DGNS-GW significantly reduced hepatic inflammation and stimulated extracellular matrix remodeling in experimental liver fibrosis.https://www.mdpi.com/1999-4923/15/5/1452liverinflammationfibrosisgraphene nanostars |
| spellingShingle | Alazne Moreno-Lanceta Mireia Medrano-Bosch Blanca Simón-Codina Montserrat Barber-González Wladimiro Jiménez Pedro Melgar-Lesmes PPAR-γ Agonist GW1929 Targeted to Macrophages with Dendrimer–Graphene Nanostars Reduces Liver Fibrosis and Inflammation Pharmaceutics liver inflammation fibrosis graphene nanostars |
| title | PPAR-γ Agonist GW1929 Targeted to Macrophages with Dendrimer–Graphene Nanostars Reduces Liver Fibrosis and Inflammation |
| title_full | PPAR-γ Agonist GW1929 Targeted to Macrophages with Dendrimer–Graphene Nanostars Reduces Liver Fibrosis and Inflammation |
| title_fullStr | PPAR-γ Agonist GW1929 Targeted to Macrophages with Dendrimer–Graphene Nanostars Reduces Liver Fibrosis and Inflammation |
| title_full_unstemmed | PPAR-γ Agonist GW1929 Targeted to Macrophages with Dendrimer–Graphene Nanostars Reduces Liver Fibrosis and Inflammation |
| title_short | PPAR-γ Agonist GW1929 Targeted to Macrophages with Dendrimer–Graphene Nanostars Reduces Liver Fibrosis and Inflammation |
| title_sort | ppar γ agonist gw1929 targeted to macrophages with dendrimer graphene nanostars reduces liver fibrosis and inflammation |
| topic | liver inflammation fibrosis graphene nanostars |
| url | https://www.mdpi.com/1999-4923/15/5/1452 |
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