SerpinB3 promotes pro-fibrogenic responses in activated hepatic stellate cells

Erica Novo; Gianmarco Villano; Cristian Turato; Stefania Cannito; Claudia Paternostro; Chiara Busletta; Alessandra Biasiolo; Santina Quarta; Elisabetta Morello; Claudia Bocca; Antonella Miglietta; Ezio David; Salvatore Sutti; Mario Plebani; Emanuele Albano; Maurizio Parola; Patrizia Pontisso

doi:10.1038/s41598-017-03744-3

SerpinB3 promotes pro-fibrogenic responses in activated hepatic stellate cells

Erica Novo
, Gianmarco Villano
, Cristian Turato
, Stefania Cannito
, Claudia Paternostro
, Chiara Busletta
, Alessandra Biasiolo
, Santina Quarta
, Elisabetta Morello
, Claudia Bocca
, Antonella Miglietta
, Ezio David
, Salvatore Sutti
, Mario Plebani
, Emanuele Albano
, Maurizio Parola
, Patrizia Pontisso

Department of Health Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

SerpinB3 is a hypoxia- and hypoxia-inducible factor-2α-dependent cystein protease inhibitor that is up-regulated in hepatocellular carcinoma and in parenchymal cells during chronic liver diseases (CLD). SerpinB3 up-regulation in CLD patients has been reported to correlate with the extent of liver fibrosis and the production of transforming growth factor-β1, but the actual role of SerpinB3 in hepatic fibrogenesis is still poorly characterized. In the present study we analyzed the pro-fibrogenic action of SerpinB3 in cell cultures and in two different murine models of liver fibrosis. "In vitro" experiments revealed that SerpinB3 addition to either primary cultures of human activated myofibroblast-like hepatic stellate cells (HSC/MFs) or human stellate cell line (LX2 cells) strongly up-regulated the expression of genes involved in fibrogenesis and promoted oriented migration, but not cell proliferation. Chronic liver injury by CCl4 administration or by feeding a methionine/choline deficient diet to transgenic mice over-expressing human SerpinB3 in hepatocytes confirmed that SerpinB3 over-expression significantly increased the mRNA levels of pro-fibrogenic genes, collagen deposition and αSMA-positive HSC/MFs as compared to wild-type mice, without affecting parenchymal damage. The present study provides for the first time evidence that hepatocyte release of SerpinB3 during CLD can contribute to liver fibrogenesis by acting on HSC/MFs.

Original language	English
Article number	3420
Journal	Scientific Reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-03744-3
Publication status	Published - 1 Dec 2017

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SDG 3 Good Health and Well-being

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10.1038/s41598-017-03744-3

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Novo, E., Villano, G., Turato, C., Cannito, S., Paternostro, C., Busletta, C., Biasiolo, A., Quarta, S., Morello, E., Bocca, C., Miglietta, A., David, E., Sutti, S., Plebani, M., Albano, E., Parola, M., & Pontisso, P. (2017). SerpinB3 promotes pro-fibrogenic responses in activated hepatic stellate cells. Scientific Reports, 7(1), Article 3420. https://doi.org/10.1038/s41598-017-03744-3

@article{42164890f1b84f6297272019db6aeb80,

title = "SerpinB3 promotes pro-fibrogenic responses in activated hepatic stellate cells",

abstract = "SerpinB3 is a hypoxia- and hypoxia-inducible factor-2α-dependent cystein protease inhibitor that is up-regulated in hepatocellular carcinoma and in parenchymal cells during chronic liver diseases (CLD). SerpinB3 up-regulation in CLD patients has been reported to correlate with the extent of liver fibrosis and the production of transforming growth factor-β1, but the actual role of SerpinB3 in hepatic fibrogenesis is still poorly characterized. In the present study we analyzed the pro-fibrogenic action of SerpinB3 in cell cultures and in two different murine models of liver fibrosis. {"}In vitro{"} experiments revealed that SerpinB3 addition to either primary cultures of human activated myofibroblast-like hepatic stellate cells (HSC/MFs) or human stellate cell line (LX2 cells) strongly up-regulated the expression of genes involved in fibrogenesis and promoted oriented migration, but not cell proliferation. Chronic liver injury by CCl4 administration or by feeding a methionine/choline deficient diet to transgenic mice over-expressing human SerpinB3 in hepatocytes confirmed that SerpinB3 over-expression significantly increased the mRNA levels of pro-fibrogenic genes, collagen deposition and αSMA-positive HSC/MFs as compared to wild-type mice, without affecting parenchymal damage. The present study provides for the first time evidence that hepatocyte release of SerpinB3 during CLD can contribute to liver fibrogenesis by acting on HSC/MFs.",

author = "Erica Novo and Gianmarco Villano and Cristian Turato and Stefania Cannito and Claudia Paternostro and Chiara Busletta and Alessandra Biasiolo and Santina Quarta and Elisabetta Morello and Claudia Bocca and Antonella Miglietta and Ezio David and Salvatore Sutti and Mario Plebani and Emanuele Albano and Maurizio Parola and Patrizia Pontisso",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2017.",

year = "2017",

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doi = "10.1038/s41598-017-03744-3",

language = "English",

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Novo, E, Villano, G, Turato, C, Cannito, S, Paternostro, C, Busletta, C, Biasiolo, A, Quarta, S, Morello, E, Bocca, C, Miglietta, A, David, E, Sutti, S, Plebani, M, Albano, E, Parola, M & Pontisso, P 2017, 'SerpinB3 promotes pro-fibrogenic responses in activated hepatic stellate cells', Scientific Reports, vol. 7, no. 1, 3420. https://doi.org/10.1038/s41598-017-03744-3

TY - JOUR

T1 - SerpinB3 promotes pro-fibrogenic responses in activated hepatic stellate cells

AU - Novo, Erica

AU - Villano, Gianmarco

AU - Turato, Cristian

AU - Cannito, Stefania

AU - Paternostro, Claudia

AU - Busletta, Chiara

AU - Biasiolo, Alessandra

AU - Quarta, Santina

AU - Morello, Elisabetta

AU - Bocca, Claudia

AU - Miglietta, Antonella

AU - David, Ezio

AU - Sutti, Salvatore

AU - Plebani, Mario

AU - Albano, Emanuele

AU - Parola, Maurizio

AU - Pontisso, Patrizia

PY - 2017/12/1

Y1 - 2017/12/1

N2 - SerpinB3 is a hypoxia- and hypoxia-inducible factor-2α-dependent cystein protease inhibitor that is up-regulated in hepatocellular carcinoma and in parenchymal cells during chronic liver diseases (CLD). SerpinB3 up-regulation in CLD patients has been reported to correlate with the extent of liver fibrosis and the production of transforming growth factor-β1, but the actual role of SerpinB3 in hepatic fibrogenesis is still poorly characterized. In the present study we analyzed the pro-fibrogenic action of SerpinB3 in cell cultures and in two different murine models of liver fibrosis. "In vitro" experiments revealed that SerpinB3 addition to either primary cultures of human activated myofibroblast-like hepatic stellate cells (HSC/MFs) or human stellate cell line (LX2 cells) strongly up-regulated the expression of genes involved in fibrogenesis and promoted oriented migration, but not cell proliferation. Chronic liver injury by CCl4 administration or by feeding a methionine/choline deficient diet to transgenic mice over-expressing human SerpinB3 in hepatocytes confirmed that SerpinB3 over-expression significantly increased the mRNA levels of pro-fibrogenic genes, collagen deposition and αSMA-positive HSC/MFs as compared to wild-type mice, without affecting parenchymal damage. The present study provides for the first time evidence that hepatocyte release of SerpinB3 during CLD can contribute to liver fibrogenesis by acting on HSC/MFs.

AB - SerpinB3 is a hypoxia- and hypoxia-inducible factor-2α-dependent cystein protease inhibitor that is up-regulated in hepatocellular carcinoma and in parenchymal cells during chronic liver diseases (CLD). SerpinB3 up-regulation in CLD patients has been reported to correlate with the extent of liver fibrosis and the production of transforming growth factor-β1, but the actual role of SerpinB3 in hepatic fibrogenesis is still poorly characterized. In the present study we analyzed the pro-fibrogenic action of SerpinB3 in cell cultures and in two different murine models of liver fibrosis. "In vitro" experiments revealed that SerpinB3 addition to either primary cultures of human activated myofibroblast-like hepatic stellate cells (HSC/MFs) or human stellate cell line (LX2 cells) strongly up-regulated the expression of genes involved in fibrogenesis and promoted oriented migration, but not cell proliferation. Chronic liver injury by CCl4 administration or by feeding a methionine/choline deficient diet to transgenic mice over-expressing human SerpinB3 in hepatocytes confirmed that SerpinB3 over-expression significantly increased the mRNA levels of pro-fibrogenic genes, collagen deposition and αSMA-positive HSC/MFs as compared to wild-type mice, without affecting parenchymal damage. The present study provides for the first time evidence that hepatocyte release of SerpinB3 during CLD can contribute to liver fibrogenesis by acting on HSC/MFs.

UR - https://www.scopus.com/pages/publications/85020536382

U2 - 10.1038/s41598-017-03744-3

DO - 10.1038/s41598-017-03744-3

M3 - Article

SN - 2045-2322

VL - 7

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 3420

ER -

SerpinB3 promotes pro-fibrogenic responses in activated hepatic stellate cells

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