SerpinB3 Promotes Pro-fibrogenic Responses in Activated Hepatic Stellate Cells

• Published in: Scientific reports Vol. 7; no. 1; pp. 3420 - 10
• Main Authors: Novo, Erica, Villano, Gianmarco, Turato, Cristian, Cannito, Stefania, Paternostro, Claudia, Busletta, Chiara, Biasiolo, Alessandra, Quarta, Santina, Morello, Elisabetta, Bocca, Claudia, Miglietta, Antonella, David, Ezio, Sutti, Salvatore, Plebani, Mario, Albano, Emanuele, Parola, Maurizio, Pontisso, Patrizia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-06-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/31; 13/51; 13/95; 14; 38; 631/80/84/1372; 692/699/1503/1607/1605; 82/80; Animal models; Animals; Cell Line; Cell proliferation; Cells, Cultured; Choline; Collagen; Collagen - genetics; Collagen - metabolism; Fibrosis; Gene expression; Hep G2 Cells; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; Hepatocellular carcinoma; Hepatocytes; Humanities and Social Sciences; Humans; Hypoxia; Hypoxia-inducible factors; Liver; Liver Cirrhosis - metabolism; Liver diseases; Methionine; Mice; Mice, Inbred C57BL; mRNA; multidisciplinary; Overexpression; Proteinase inhibitors; Rodents; Science; Science (multidisciplinary); Serpins - genetics; Serpins - metabolism; Serpins - pharmacology; Stellate cells; Transgenic mice
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-03744-3

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 CCl
4
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.