The protease activated receptor 2 - CCAAT/enhancer-binding protein beta - SerpinB3 axis inhibition as a novel strategy for the treatment of non-alcoholic steatohepatitis
Objective: The serine protease inhibitor SerpinB3 has been described as critical mediator of liver fibrosis and it has been recently proposed as an additional hepatokine involved in NASH development and insulin resistance. Protease Activated Receptor 2 has been identified as a novel regulator of hep...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-03-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877824000206 |
| _version_ | 1797272499733397504 |
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| author | Gianmarco Villano Erica Novo Cristian Turato Santina Quarta Mariagrazia Ruvoletto Alessandra Biasiolo Francesca Protopapa Monica Chinellato Andrea Martini Elisabetta Trevellin Marnie Granzotto Stefania Cannito Laura Cendron Silvia De Siervi Maria Guido Maurizio Parola Roberto Vettor Patrizia Pontisso |
| author_facet | Gianmarco Villano Erica Novo Cristian Turato Santina Quarta Mariagrazia Ruvoletto Alessandra Biasiolo Francesca Protopapa Monica Chinellato Andrea Martini Elisabetta Trevellin Marnie Granzotto Stefania Cannito Laura Cendron Silvia De Siervi Maria Guido Maurizio Parola Roberto Vettor Patrizia Pontisso |
| author_sort | Gianmarco Villano |
| collection | DOAJ |
| description | Objective: The serine protease inhibitor SerpinB3 has been described as critical mediator of liver fibrosis and it has been recently proposed as an additional hepatokine involved in NASH development and insulin resistance. Protease Activated Receptor 2 has been identified as a novel regulator of hepatic metabolism. A targeted therapeutic strategy for NASH has been investigated, using 1-Piperidine Propionic Acid (1-PPA), since this compound has been recently proposed as both Protease Activated Receptor 2 and SerpinB3 inhibitor. Methods: The effect of SerpinB3 on inflammation and fibrosis genes was assessed in human macrophage and stellate cell lines. Transgenic mice, either overexpressing SerpinB3 or carrying Serpinb3 deletion and their relative wild type strains, were used in experimental NASH models. Subgroups of SerpinB3 transgenic mice and their controls were also injected with 1-PPA to assess the efficacy of this compound in NASH inhibition. Results: 1-PPA did not present significant cell and organ toxicity and was able to inhibit SerpinB3 and PAR2 in a dose-dependent manner. This effect was associated to a parallel reduction of the synthesis of the molecules induced by endogenous SerpinB3 or by its paracrine effects both in vitro and in vivo, leading to inhibition of lipid accumulation, inflammation and fibrosis in experimental NASH. At mechanistic level, the antiprotease activity of SerpinB3 was found essential for PAR2 activation, determining upregulation of the CCAAT Enhancer Binding Protein beta (C/EBP-β), another pivotal regulator of metabolism, inflammation and fibrosis, which in turn determined SerpinB3 synthesis. Conclusions: 1-PPA treatment was able to inhibit the PAR2 - C/EBP-β - SerpinB3 axis and to protect from NASH development and progression, supporting the potential use of a similar approach for a targeted therapy of NASH. |
| first_indexed | 2024-03-07T14:29:14Z |
| format | Article |
| id | doaj.art-945f4fb8656c43e38474dd471095687a |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-03-07T14:29:14Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-945f4fb8656c43e38474dd471095687a2024-03-06T05:26:40ZengElsevierMolecular Metabolism2212-87782024-03-0181101889The protease activated receptor 2 - CCAAT/enhancer-binding protein beta - SerpinB3 axis inhibition as a novel strategy for the treatment of non-alcoholic steatohepatitisGianmarco Villano0Erica Novo1Cristian Turato2Santina Quarta3Mariagrazia Ruvoletto4Alessandra Biasiolo5Francesca Protopapa6Monica Chinellato7Andrea Martini8Elisabetta Trevellin9Marnie Granzotto10Stefania Cannito11Laura Cendron12Silvia De Siervi13Maria Guido14Maurizio Parola15Roberto Vettor16Patrizia Pontisso17Dept. of Surgical, Oncological and Gastroenterological Sciences, University of Padova, ItalyDept. of Clinical and Biological Sciences, University of Torino, ItalyDept. of Molecular Medicine, University of Pavia, ItalyDept. of Medicine, University of Padova, ItalyDept. of Medicine, University of Padova, ItalyDept. of Medicine, University of Padova, ItalyDept. of Clinical and Biological Sciences, University of Torino, ItalyDept. of Medicine, University of Padova, ItalyDept. of Medicine, University of Padova, ItalyDept. of Medicine, University of Padova, ItalyDept. of Medicine, University of Padova, ItalyDept. of Clinical and Biological Sciences, University of Torino, ItalyDept. of Biology, University of Padova, ItalyDept. of Molecular Medicine, University of Pavia, ItalyDept. of Medicine, University of Padova, ItalyDept. of Clinical and Biological Sciences, University of Torino, ItalyDept. of Medicine, University of Padova, ItalyDept. of Medicine, University of Padova, Italy; Corresponding author. Dept. of Medicine, University of Padova, Via Giustiniani 2 35128 Padova, Italy. Tel.: +39 049 8217872.Objective: The serine protease inhibitor SerpinB3 has been described as critical mediator of liver fibrosis and it has been recently proposed as an additional hepatokine involved in NASH development and insulin resistance. Protease Activated Receptor 2 has been identified as a novel regulator of hepatic metabolism. A targeted therapeutic strategy for NASH has been investigated, using 1-Piperidine Propionic Acid (1-PPA), since this compound has been recently proposed as both Protease Activated Receptor 2 and SerpinB3 inhibitor. Methods: The effect of SerpinB3 on inflammation and fibrosis genes was assessed in human macrophage and stellate cell lines. Transgenic mice, either overexpressing SerpinB3 or carrying Serpinb3 deletion and their relative wild type strains, were used in experimental NASH models. Subgroups of SerpinB3 transgenic mice and their controls were also injected with 1-PPA to assess the efficacy of this compound in NASH inhibition. Results: 1-PPA did not present significant cell and organ toxicity and was able to inhibit SerpinB3 and PAR2 in a dose-dependent manner. This effect was associated to a parallel reduction of the synthesis of the molecules induced by endogenous SerpinB3 or by its paracrine effects both in vitro and in vivo, leading to inhibition of lipid accumulation, inflammation and fibrosis in experimental NASH. At mechanistic level, the antiprotease activity of SerpinB3 was found essential for PAR2 activation, determining upregulation of the CCAAT Enhancer Binding Protein beta (C/EBP-β), another pivotal regulator of metabolism, inflammation and fibrosis, which in turn determined SerpinB3 synthesis. Conclusions: 1-PPA treatment was able to inhibit the PAR2 - C/EBP-β - SerpinB3 axis and to protect from NASH development and progression, supporting the potential use of a similar approach for a targeted therapy of NASH.http://www.sciencedirect.com/science/article/pii/S2212877824000206SerpinsGenetically manipulated miceExperimental NASHTranscription factorsTherapeutic drugs |
| spellingShingle | Gianmarco Villano Erica Novo Cristian Turato Santina Quarta Mariagrazia Ruvoletto Alessandra Biasiolo Francesca Protopapa Monica Chinellato Andrea Martini Elisabetta Trevellin Marnie Granzotto Stefania Cannito Laura Cendron Silvia De Siervi Maria Guido Maurizio Parola Roberto Vettor Patrizia Pontisso The protease activated receptor 2 - CCAAT/enhancer-binding protein beta - SerpinB3 axis inhibition as a novel strategy for the treatment of non-alcoholic steatohepatitis Molecular Metabolism Serpins Genetically manipulated mice Experimental NASH Transcription factors Therapeutic drugs |
| title | The protease activated receptor 2 - CCAAT/enhancer-binding protein beta - SerpinB3 axis inhibition as a novel strategy for the treatment of non-alcoholic steatohepatitis |
| title_full | The protease activated receptor 2 - CCAAT/enhancer-binding protein beta - SerpinB3 axis inhibition as a novel strategy for the treatment of non-alcoholic steatohepatitis |
| title_fullStr | The protease activated receptor 2 - CCAAT/enhancer-binding protein beta - SerpinB3 axis inhibition as a novel strategy for the treatment of non-alcoholic steatohepatitis |
| title_full_unstemmed | The protease activated receptor 2 - CCAAT/enhancer-binding protein beta - SerpinB3 axis inhibition as a novel strategy for the treatment of non-alcoholic steatohepatitis |
| title_short | The protease activated receptor 2 - CCAAT/enhancer-binding protein beta - SerpinB3 axis inhibition as a novel strategy for the treatment of non-alcoholic steatohepatitis |
| title_sort | protease activated receptor 2 ccaat enhancer binding protein beta serpinb3 axis inhibition as a novel strategy for the treatment of non alcoholic steatohepatitis |
| topic | Serpins Genetically manipulated mice Experimental NASH Transcription factors Therapeutic drugs |
| url | http://www.sciencedirect.com/science/article/pii/S2212877824000206 |
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