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PPAR-γ Agonist GW1929 Targeted to Macrophages with Dendrimer-Graphene Nanostars Reduces Liver Fibrosis and
Alazne Moreno-Lanceta1,2, Mireia Medrano-Bosch1, Blanca Simón-Codina1
1Department of Biomedicine, School of Medicine, University of Barcelona, 08036 Barcelona, Spain.
Abstract:
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.
Insights
Novel nanostar drug delivery targets macrophages, activating PPARγ to reduce liver inflammation and fibrosis. This approach selectively reduces liver damage without affecting liver function.
Area of Science:
- Immunology
- Nanotechnology
- Hepatology
Background:
- Macrophages are key players in chronic liver disease, influencing fibrogenesis and regression.
- PPARγ activation in macrophages typically confers anti-inflammatory properties, but selective agonists are lacking.
- Existing PPARγ agonists have severe side effects, limiting their clinical use.
Purpose of the Study:
- To develop a targeted drug delivery system for selective PPARγ activation in macrophages within fibrotic livers.
- To investigate the therapeutic potential of DGNS-GW in reducing liver inflammation and fibrosis.
Main Methods:
- Design of dendrimer-graphene nanostars linked to a low dose of GW1929 PPARγ agonist (DGNS-GW).
- In vitro assessment of DGNS-GW accumulation and effect on macrophage phenotype.
- In vivo treatment of fibrotic mice with DGNS-GW to evaluate liver PPARγ signaling, macrophage polarization, inflammation, and fibrosis.
Main Results:
- DGNS-GW preferentially accumulated in inflammatory macrophages in vitro, attenuating their pro-inflammatory phenotype.
- In vivo, DGNS-GW activated liver PPARγ signaling, shifting macrophages from M1 to M2 phenotype.
- Treatment significantly reduced hepatic inflammation and fibrosis by promoting extracellular matrix remodeling via metalloproteinase expression, without altering liver function.
Conclusions:
- Selective activation of PPARγ in hepatic macrophages using DGNS-GW effectively reduces liver inflammation and fibrosis.
- The therapeutic strategy promotes extracellular matrix remodeling, offering a promising approach for treating experimental liver fibrosis.
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