AQP3 is regulated by PPARγ and JNK in hepatic stellate cells carrying PNPLA3 I148M
Abstract Aquaglyceroporins (AQPs) allow the movement of glycerol that is required for triglyceride formation in hepatic stellate cells (HSC), as key cellular source of fibrogenesis in the liver. The genetic polymorphism I148M of the patatin-like phospholipase domain-containing 3 (PNPLA3) is associat...
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doaj-8b73a292eb56472ba1d21a8fd55ac4552020-12-08T02:44:46ZengNature Publishing GroupScientific Reports2045-23222017-11-017111010.1038/s41598-017-14557-9AQP3 is regulated by PPARγ and JNK in hepatic stellate cells carrying PNPLA3 I148MMatteo Tardelli0Francesca V. Bruschi1Thierry Claudel2Veronica Moreno-Viedma3Emina Halilbasic4Fabio Marra5Merima Herac6Thomas M. Stulnig7Michael Trauner8Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology & Hepatology, Internal Medicine III, Medical University of ViennaHans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology & Hepatology, Internal Medicine III, Medical University of ViennaHans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology & Hepatology, Internal Medicine III, Medical University of ViennaChristian Doppler-Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Internal Medicine III, Medical University of ViennaHans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology & Hepatology, Internal Medicine III, Medical University of ViennaDepartment of Experimental and Clinical Medicine, University of FlorenceClinical Institute of Pathology, Medical University of ViennaChristian Doppler-Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Internal Medicine III, Medical University of ViennaHans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology & Hepatology, Internal Medicine III, Medical University of ViennaAbstract Aquaglyceroporins (AQPs) allow the movement of glycerol that is required for triglyceride formation in hepatic stellate cells (HSC), as key cellular source of fibrogenesis in the liver. The genetic polymorphism I148M of the patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with hepatic steatosis and its progression to steatohepatitis (NASH), fibrosis and cancer. We aimed to explore the role of AQP3 for HSC activation and unveil its potential interactions with PNPLA3. HSC were isolated from human liver, experiments were performed in primary HSC and human HSC line LX2. AQP3 was the only aquaglyceroporin present in HSC and its expression decreased during activation. The PPARγ agonist, rosiglitazone, recovered AQP3 expression also in PNPLA3 I148M carrying HSC. When PNPLA3 was silenced, AQP3 expression increased. In liver sections from patients with NASH, the decreased amount of AQP3 was proportional to the severity of fibrosis and presence of the PNPLA3 I148M variant. In PNPLA3 I148M cells, the blockade of JNK pathway upregulated AQP3 in synergism with PPARγ. In conclusion, we demonstrated profound reduction of AQP3 in HSC carrying the PNPLA3 I148M variant in parallel to decreased PPARγ activation, which could be rescued by rosiglitazone and blockade of JNK.https://doi.org/10.1038/s41598-017-14557-9 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Matteo Tardelli Francesca V. Bruschi Thierry Claudel Veronica Moreno-Viedma Emina Halilbasic Fabio Marra Merima Herac Thomas M. Stulnig Michael Trauner |
spellingShingle |
Matteo Tardelli Francesca V. Bruschi Thierry Claudel Veronica Moreno-Viedma Emina Halilbasic Fabio Marra Merima Herac Thomas M. Stulnig Michael Trauner AQP3 is regulated by PPARγ and JNK in hepatic stellate cells carrying PNPLA3 I148M Scientific Reports |
author_facet |
Matteo Tardelli Francesca V. Bruschi Thierry Claudel Veronica Moreno-Viedma Emina Halilbasic Fabio Marra Merima Herac Thomas M. Stulnig Michael Trauner |
author_sort |
Matteo Tardelli |
title |
AQP3 is regulated by PPARγ and JNK in hepatic stellate cells carrying PNPLA3 I148M |
title_short |
AQP3 is regulated by PPARγ and JNK in hepatic stellate cells carrying PNPLA3 I148M |
title_full |
AQP3 is regulated by PPARγ and JNK in hepatic stellate cells carrying PNPLA3 I148M |
title_fullStr |
AQP3 is regulated by PPARγ and JNK in hepatic stellate cells carrying PNPLA3 I148M |
title_full_unstemmed |
AQP3 is regulated by PPARγ and JNK in hepatic stellate cells carrying PNPLA3 I148M |
title_sort |
aqp3 is regulated by pparγ and jnk in hepatic stellate cells carrying pnpla3 i148m |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-11-01 |
description |
Abstract Aquaglyceroporins (AQPs) allow the movement of glycerol that is required for triglyceride formation in hepatic stellate cells (HSC), as key cellular source of fibrogenesis in the liver. The genetic polymorphism I148M of the patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with hepatic steatosis and its progression to steatohepatitis (NASH), fibrosis and cancer. We aimed to explore the role of AQP3 for HSC activation and unveil its potential interactions with PNPLA3. HSC were isolated from human liver, experiments were performed in primary HSC and human HSC line LX2. AQP3 was the only aquaglyceroporin present in HSC and its expression decreased during activation. The PPARγ agonist, rosiglitazone, recovered AQP3 expression also in PNPLA3 I148M carrying HSC. When PNPLA3 was silenced, AQP3 expression increased. In liver sections from patients with NASH, the decreased amount of AQP3 was proportional to the severity of fibrosis and presence of the PNPLA3 I148M variant. In PNPLA3 I148M cells, the blockade of JNK pathway upregulated AQP3 in synergism with PPARγ. In conclusion, we demonstrated profound reduction of AQP3 in HSC carrying the PNPLA3 I148M variant in parallel to decreased PPARγ activation, which could be rescued by rosiglitazone and blockade of JNK. |
url |
https://doi.org/10.1038/s41598-017-14557-9 |
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