PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis

Liver fibrosis is a pathological scarring response to chronic hepatocellular injury and hepatic stellate cells (HSCs) are key players in this process. PNPLA3 I148M is a common variant robustly associated with liver fibrosis but the mechanisms underlying this association are unknown. We aimed to exam...

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Autores principales: Pingitore, Piero, Dongiovanni, Paola, Motta, Benedetta Maria, Meroni, Marica, Lepore, Saverio Massimo, Mancina, Rosellina Margherita, Pelusi, Serena, Russo, Cristina, Caddeo, Andrea, Rossi, Giorgio, Montalcini, Tiziana, Pujia, Arturo, Wiklund, Olov, Valenti, Luca, Romeo, Stefano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886043/
https://www.ncbi.nlm.nih.gov/pubmed/27742777
http://dx.doi.org/10.1093/hmg/ddw341
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author Pingitore, Piero
Dongiovanni, Paola
Motta, Benedetta Maria
Meroni, Marica
Lepore, Saverio Massimo
Mancina, Rosellina Margherita
Pelusi, Serena
Russo, Cristina
Caddeo, Andrea
Rossi, Giorgio
Montalcini, Tiziana
Pujia, Arturo
Wiklund, Olov
Valenti, Luca
Romeo, Stefano
author_facet Pingitore, Piero
Dongiovanni, Paola
Motta, Benedetta Maria
Meroni, Marica
Lepore, Saverio Massimo
Mancina, Rosellina Margherita
Pelusi, Serena
Russo, Cristina
Caddeo, Andrea
Rossi, Giorgio
Montalcini, Tiziana
Pujia, Arturo
Wiklund, Olov
Valenti, Luca
Romeo, Stefano
author_sort Pingitore, Piero
collection PubMed
description Liver fibrosis is a pathological scarring response to chronic hepatocellular injury and hepatic stellate cells (HSCs) are key players in this process. PNPLA3 I148M is a common variant robustly associated with liver fibrosis but the mechanisms underlying this association are unknown. We aimed to examine a) the effect of fibrogenic and proliferative stimuli on PNPLA3 levels in HSCs and b) the role of wild type and mutant PNPLA3 overexpression on markers of HSC activation and fibrosis. Here, we show that PNPLA3 is upregulated by the fibrogenic cytokine transforming growth factor-beta (TGF-β), but not by platelet-derived growth factor (PDGF), and is involved in the TGF-β-induced reduction in lipid droplets in primary human HSCs. Furthermore, we show that retinol release from human HSCs ex vivo is lower in cells with the loss-of-function PNPLA3 148M compared with 148I wild type protein. Stable overexpression of PNPLA3 148I wild type, but not 148M mutant, in human HSCs (LX-2 cells) induces a reduction in the secretion of matrix metallopeptidase 2 (MMP2), tissue inhibitor of metalloproteinase 1 and 2 (TIMP1 and TIMP2), which is mediated by retinoid metabolism. In conclusion, we show a role for PNPLA3 in HSC activation in response to fibrogenic stimuli. Moreover, we provide evidence to indicate that PNPLA3-mediated retinol release may protect against liver fibrosis by inducing a specific signature of proteins involved in extracellular matrix remodelling.
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spelling pubmed-58860432018-04-09 PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis Pingitore, Piero Dongiovanni, Paola Motta, Benedetta Maria Meroni, Marica Lepore, Saverio Massimo Mancina, Rosellina Margherita Pelusi, Serena Russo, Cristina Caddeo, Andrea Rossi, Giorgio Montalcini, Tiziana Pujia, Arturo Wiklund, Olov Valenti, Luca Romeo, Stefano Hum Mol Genet Articles Liver fibrosis is a pathological scarring response to chronic hepatocellular injury and hepatic stellate cells (HSCs) are key players in this process. PNPLA3 I148M is a common variant robustly associated with liver fibrosis but the mechanisms underlying this association are unknown. We aimed to examine a) the effect of fibrogenic and proliferative stimuli on PNPLA3 levels in HSCs and b) the role of wild type and mutant PNPLA3 overexpression on markers of HSC activation and fibrosis. Here, we show that PNPLA3 is upregulated by the fibrogenic cytokine transforming growth factor-beta (TGF-β), but not by platelet-derived growth factor (PDGF), and is involved in the TGF-β-induced reduction in lipid droplets in primary human HSCs. Furthermore, we show that retinol release from human HSCs ex vivo is lower in cells with the loss-of-function PNPLA3 148M compared with 148I wild type protein. Stable overexpression of PNPLA3 148I wild type, but not 148M mutant, in human HSCs (LX-2 cells) induces a reduction in the secretion of matrix metallopeptidase 2 (MMP2), tissue inhibitor of metalloproteinase 1 and 2 (TIMP1 and TIMP2), which is mediated by retinoid metabolism. In conclusion, we show a role for PNPLA3 in HSC activation in response to fibrogenic stimuli. Moreover, we provide evidence to indicate that PNPLA3-mediated retinol release may protect against liver fibrosis by inducing a specific signature of proteins involved in extracellular matrix remodelling. Oxford University Press 2016-12-01 2016-10-13 /pmc/articles/PMC5886043/ /pubmed/27742777 http://dx.doi.org/10.1093/hmg/ddw341 Text en © The Author 2016. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Articles
Pingitore, Piero
Dongiovanni, Paola
Motta, Benedetta Maria
Meroni, Marica
Lepore, Saverio Massimo
Mancina, Rosellina Margherita
Pelusi, Serena
Russo, Cristina
Caddeo, Andrea
Rossi, Giorgio
Montalcini, Tiziana
Pujia, Arturo
Wiklund, Olov
Valenti, Luca
Romeo, Stefano
PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis
title PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis
title_full PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis
title_fullStr PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis
title_full_unstemmed PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis
title_short PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis
title_sort pnpla3 overexpression results in reduction of proteins predisposing to fibrosis
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886043/
https://www.ncbi.nlm.nih.gov/pubmed/27742777
http://dx.doi.org/10.1093/hmg/ddw341
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