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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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Autores principales: Moreno-Lanceta, Alazne, Medrano-Bosch, Mireia, Simón-Codina, Blanca, Barber-González, Montserrat, Jiménez, Wladimiro, Melgar-Lesmes, Pedro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10223394/
https://www.ncbi.nlm.nih.gov/pubmed/37242695
http://dx.doi.org/10.3390/pharmaceutics15051452
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author Moreno-Lanceta, Alazne
Medrano-Bosch, Mireia
Simón-Codina, Blanca
Barber-González, Montserrat
Jiménez, Wladimiro
Melgar-Lesmes, Pedro
author_facet Moreno-Lanceta, Alazne
Medrano-Bosch, Mireia
Simón-Codina, Blanca
Barber-González, Montserrat
Jiménez, Wladimiro
Melgar-Lesmes, Pedro
author_sort Moreno-Lanceta, Alazne
collection PubMed
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.
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spelling pubmed-102233942023-05-28 PPAR-γ Agonist GW1929 Targeted to Macrophages with Dendrimer–Graphene Nanostars Reduces Liver Fibrosis and Inflammation Moreno-Lanceta, Alazne Medrano-Bosch, Mireia Simón-Codina, Blanca Barber-González, Montserrat Jiménez, Wladimiro Melgar-Lesmes, Pedro Pharmaceutics Article 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. MDPI 2023-05-10 /pmc/articles/PMC10223394/ /pubmed/37242695 http://dx.doi.org/10.3390/pharmaceutics15051452 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Moreno-Lanceta, Alazne
Medrano-Bosch, Mireia
Simón-Codina, Blanca
Barber-González, Montserrat
Jiménez, Wladimiro
Melgar-Lesmes, Pedro
PPAR-γ Agonist GW1929 Targeted to Macrophages with Dendrimer–Graphene Nanostars Reduces Liver Fibrosis and Inflammation
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10223394/
https://www.ncbi.nlm.nih.gov/pubmed/37242695
http://dx.doi.org/10.3390/pharmaceutics15051452
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