Martins, Maria Castanho;
Dixon, Emmanuel Dauda;
Lupo, Giulia;
Claudel, Thierry;
Trauner, Michael;
Rombouts, Krista;
(2025)
Role of PNPLA3 in Hepatic Stellate Cells and Hepatic
Cellular Crosstalk.
Liver International
, 45
(4)
, Article e16117. 10.1111/liv.16117.
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Abstract
Aims: Since its discovery, the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C>G p.I148M) variant has been studied extensively to unravel its molecular function. Although several studies proved a causal relationship between the PNPLA3 I148M variant and MASLD development and particularly fibrosis, the pathological mechanisms promoting this phenotype have not yet been fully clarified. / / Methods: We summarise the latest data regarding the PNPLA3 I148M variant in hepatic stellate cells (HSCs) activation and macrophage biology or the path to inflammation-induced fibrosis. / / Results: Elegant but contradictory studies have ascribed PNPLA3 a hydrolase or an acyltransferase function. The PNPLA3 I148M results in hepatic lipid accumulation, which predisposes the hepatocyte to lipotoxicity and lipo-apoptosis, producing DAMPs, cytokines and chemokines leading to recruitment and activation of macrophages and HSCs, propagating fibrosis. Recent studies showed that the PNPLA3 I148M variant alters HSCs biology via attenuation of PPARγ, AP-1, LXRα and TGFβ activity and signalling. / / Conclusions: The advent of refined techniques in isolating HSCs has made PNPLA3's direct role in HSCs for liver fibrosis development more apparent. However, many other mechanisms still need detailed investigations.
| Type: | Article |
|---|---|
| Title: | Role of PNPLA3 in Hepatic Stellate Cells and Hepatic Cellular Crosstalk |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/liv.16117 |
| Publisher version: | https://doi.org/10.1111/liv.16117 |
| Language: | English |
| Additional information: | © The Author(s), 2025. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/ |
| Keywords: | hepatic stellate cells (HSCs): patatin-like phospholipase domain containing 3 (PNPLA3), liver cirrhosis, liver fibrosis, liver inflammation, metabolic dysfunction-associated steatohepatitis (MASH), metabolic dysfunction-associated steatotic liver disease (MASLD), nuclear receptors (NR). |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10215376 |
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