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...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783312074898669568 |
---|---|
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. |
format | Online Article Text |
id | pubmed-5886043 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT pingitorepiero pnpla3overexpressionresultsinreductionofproteinspredisposingtofibrosis AT dongiovannipaola pnpla3overexpressionresultsinreductionofproteinspredisposingtofibrosis AT mottabenedettamaria pnpla3overexpressionresultsinreductionofproteinspredisposingtofibrosis AT meronimarica pnpla3overexpressionresultsinreductionofproteinspredisposingtofibrosis AT leporesaveriomassimo pnpla3overexpressionresultsinreductionofproteinspredisposingtofibrosis AT mancinarosellinamargherita pnpla3overexpressionresultsinreductionofproteinspredisposingtofibrosis AT pelusiserena pnpla3overexpressionresultsinreductionofproteinspredisposingtofibrosis AT russocristina pnpla3overexpressionresultsinreductionofproteinspredisposingtofibrosis AT caddeoandrea pnpla3overexpressionresultsinreductionofproteinspredisposingtofibrosis AT rossigiorgio pnpla3overexpressionresultsinreductionofproteinspredisposingtofibrosis AT montalcinitiziana pnpla3overexpressionresultsinreductionofproteinspredisposingtofibrosis AT pujiaarturo pnpla3overexpressionresultsinreductionofproteinspredisposingtofibrosis AT wiklundolov pnpla3overexpressionresultsinreductionofproteinspredisposingtofibrosis AT valentiluca pnpla3overexpressionresultsinreductionofproteinspredisposingtofibrosis AT romeostefano pnpla3overexpressionresultsinreductionofproteinspredisposingtofibrosis |