The protease activated receptor 2 - CCAAT/enhancer-binding protein beta - SerpinB3 axis inhibition as a novel strategy for the treatment of non-alcoholic steatohepatitis.

Autor:	Villano G; Dept. of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Italy., Novo E; Dept. of Clinical and Biological Sciences, University of Torino, Italy., Turato C; Dept. of Molecular Medicine, University of Pavia, Italy., Quarta S; Dept. of Medicine, University of Padova, Italy., Ruvoletto M; Dept. of Medicine, University of Padova, Italy., Biasiolo A; Dept. of Medicine, University of Padova, Italy., Protopapa F; Dept. of Clinical and Biological Sciences, University of Torino, Italy., Chinellato M; Dept. of Medicine, University of Padova, Italy., Martini A; Dept. of Medicine, University of Padova, Italy., Trevellin E; Dept. of Medicine, University of Padova, Italy., Granzotto M; Dept. of Medicine, University of Padova, Italy., Cannito S; Dept. of Clinical and Biological Sciences, University of Torino, Italy., Cendron L; Dept. of Biology, University of Padova, Italy., De Siervi S; Dept. of Molecular Medicine, University of Pavia, Italy., Guido M; Dept. of Medicine, University of Padova, Italy., Parola M; Dept. of Clinical and Biological Sciences, University of Torino, Italy., Vettor R; Dept. of Medicine, University of Padova, Italy., Pontisso P; Dept. of Medicine, University of Padova, Italy. Electronic address: patrizia@unipd.it.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2024 Mar; Vol. 81, pp. 101889. Date of Electronic Publication: 2024 Feb 01.
DOI:	10.1016/j.molmet.2024.101889
Abstrakt:	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. Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare that P.P., B.A., M.A., Q.S., R.M., T.C. and V.G. are listed as inventors of patent N. IT 102017000026858, European patent EP 392351 and P.P., B.A., L.C., M.C., Q.S., R.M., T.C. and V.G of the Italian Patent Application N. 102022000014593 filed by the University of Padova, PTC pending. No conflict of interest exists for the other authors. (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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