PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis

Paola Pingitore, P. Dongiovanni, B. M. Motta, M. Meroni, S. M. Lepore, Rosellina Margherita Mancina, Serena Pelusi, C. Russo, Alessandra Caddeo, Giorgio Ettore Rossi, Tiziana Montalcini, Arturo Pujia, Olov Wiklund, L. Valenti, S. Romeo

Research output: Contribution to journalArticle

Abstract

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-beta), but not by platelet-derived growth factor (PDGF), and is involved in the TGF-beta-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.
Original languageEnglish
Pages (from-to)5212-5222
Number of pages11
JournalHuman Molecular Genetics
Volume25
Issue number23
DOIs
Publication statusPublished - 2016

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    Pingitore, P., Dongiovanni, P., Motta, B. M., Meroni, M., Lepore, S. M., Mancina, R. M., Pelusi, S., Russo, C., Caddeo, A., Rossi, G. E., Montalcini, T., Pujia, A., Wiklund, O., Valenti, L., & Romeo, S. (2016). PNPLA3 overexpression results in reduction of proteins predisposing to fibrosis. Human Molecular Genetics, 25(23), 5212-5222. https://doi.org/ddw341 [pii]