Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor
Dysregulations of lipid metabolism in the liver may trigger steatosis progression, leading to potentially severe clinical consequences such as nonalcoholic fatty liver diseases (NAFLDs). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and multi...
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sg-ntu-dr.10356-1643692023-03-05T16:54:00Z Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor Personnaz, Jean Piccolo, Enzo Dortignac, Alizée Iacovoni, Jason S. Mariette, Jérôme Rocher, Vincent Polizzi, Arnaud Batut, Aurélie Deleruyelle, Simon Bourdens, Lucas Delos, Océane Combes-Soia, Lucie Paccoud, Romain Moreau, Elsa Martins, Frédéric Clouaire, Thomas Benhamed, Fadila Montagner, Alexandra Wahli, Walter Schwabe, Robert F. Yart, Armelle Castan-Laurell, Isabelle Bertrand-Michel, Justine Burlet-Schiltz, Odile Postic, Catherine Denechaud, Pierre-Damien Moro, Cédric Legube, Gaelle Lee, Chih-Hao Guillou, Hervé Valet, Philippe Dray, Cédric Pradère, Jean-Philippe Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Fatty Liver Lipid Metabolisms Dysregulations of lipid metabolism in the liver may trigger steatosis progression, leading to potentially severe clinical consequences such as nonalcoholic fatty liver diseases (NAFLDs). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis. Mice with liver-specific Hmgb1 deficiency display exacerbated liver steatosis, while Hmgb1-overexpressing mice exhibited a protection from fatty liver progression when subjected to nutritional stress. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXRα and PPARγ activity. HMGB1 repression is not mediated through nucleosome landscape reorganization but rather via a preferential DNA occupation in a region carrying genes regulated by LXRα and PPARγ. Together, these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target the LXRα-PPARγ axis during NAFLD. Published version This study was supported by grants from INSERM, Paul Sabatier University, the Agence Nationale de la Recherche (ANR-17-CE14-0016, to J.-P.P.), and the Région Occitanie and Association Française d’Etude et de Recherche sur l’Obésité (to J.-P.P.). J.P. was supported by a scholarship from Paul Sabatier University. E.P. was supported by a scholarship from Agence Nationale de la Recherche (ANR-17-CE14-0016). R.P. was supported by a scholarship from Région Midi-Pyrénées-INSERM (no. 15050341). O.B.-S. and L.C.-S. and the proteomic facility were supported, in part, by the Région Occitanie, European funds (Fonds Européens de Développement Régional, FEDER), Toulouse Métropole, and the French Ministry of Research with the Investissement d’Avenir Infrastructures Nationales en Biologie et Santé program (ProFI, Proteomics French Infrastructure project, ANR-10-INBS-08). 2023-01-18T01:51:40Z 2023-01-18T01:51:40Z 2022 Journal Article Personnaz, J., Piccolo, E., Dortignac, A., Iacovoni, J. S., Mariette, J., Rocher, V., Polizzi, A., Batut, A., Deleruyelle, S., Bourdens, L., Delos, O., Combes-Soia, L., Paccoud, R., Moreau, E., Martins, F., Clouaire, T., Benhamed, F., Montagner, A., Wahli, W., ...Pradère, J. (2022). Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor. Science Advances, 8(12), eabg9055-. https://dx.doi.org/10.1126/sciadv.abg9055 2375-2548 https://hdl.handle.net/10356/164369 10.1126/sciadv.abg9055 35333579 2-s2.0-85127261875 12 8 eabg9055 en Science Advances © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). application/pdf |
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Science::Medicine Fatty Liver Lipid Metabolisms Personnaz, Jean Piccolo, Enzo Dortignac, Alizée Iacovoni, Jason S. Mariette, Jérôme Rocher, Vincent Polizzi, Arnaud Batut, Aurélie Deleruyelle, Simon Bourdens, Lucas Delos, Océane Combes-Soia, Lucie Paccoud, Romain Moreau, Elsa Martins, Frédéric Clouaire, Thomas Benhamed, Fadila Montagner, Alexandra Wahli, Walter Schwabe, Robert F. Yart, Armelle Castan-Laurell, Isabelle Bertrand-Michel, Justine Burlet-Schiltz, Odile Postic, Catherine Denechaud, Pierre-Damien Moro, Cédric Legube, Gaelle Lee, Chih-Hao Guillou, Hervé Valet, Philippe Dray, Cédric Pradère, Jean-Philippe Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor |
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Dysregulations of lipid metabolism in the liver may trigger steatosis progression, leading to potentially severe clinical consequences such as nonalcoholic fatty liver diseases (NAFLDs). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis. Mice with liver-specific Hmgb1 deficiency display exacerbated liver steatosis, while Hmgb1-overexpressing mice exhibited a protection from fatty liver progression when subjected to nutritional stress. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXRα and PPARγ activity. HMGB1 repression is not mediated through nucleosome landscape reorganization but rather via a preferential DNA occupation in a region carrying genes regulated by LXRα and PPARγ. Together, these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target the LXRα-PPARγ axis during NAFLD. |
author2 |
Lee Kong Chian School of Medicine (LKCMedicine) |
author_facet |
Lee Kong Chian School of Medicine (LKCMedicine) Personnaz, Jean Piccolo, Enzo Dortignac, Alizée Iacovoni, Jason S. Mariette, Jérôme Rocher, Vincent Polizzi, Arnaud Batut, Aurélie Deleruyelle, Simon Bourdens, Lucas Delos, Océane Combes-Soia, Lucie Paccoud, Romain Moreau, Elsa Martins, Frédéric Clouaire, Thomas Benhamed, Fadila Montagner, Alexandra Wahli, Walter Schwabe, Robert F. Yart, Armelle Castan-Laurell, Isabelle Bertrand-Michel, Justine Burlet-Schiltz, Odile Postic, Catherine Denechaud, Pierre-Damien Moro, Cédric Legube, Gaelle Lee, Chih-Hao Guillou, Hervé Valet, Philippe Dray, Cédric Pradère, Jean-Philippe |
format |
Article |
author |
Personnaz, Jean Piccolo, Enzo Dortignac, Alizée Iacovoni, Jason S. Mariette, Jérôme Rocher, Vincent Polizzi, Arnaud Batut, Aurélie Deleruyelle, Simon Bourdens, Lucas Delos, Océane Combes-Soia, Lucie Paccoud, Romain Moreau, Elsa Martins, Frédéric Clouaire, Thomas Benhamed, Fadila Montagner, Alexandra Wahli, Walter Schwabe, Robert F. Yart, Armelle Castan-Laurell, Isabelle Bertrand-Michel, Justine Burlet-Schiltz, Odile Postic, Catherine Denechaud, Pierre-Damien Moro, Cédric Legube, Gaelle Lee, Chih-Hao Guillou, Hervé Valet, Philippe Dray, Cédric Pradère, Jean-Philippe |
author_sort |
Personnaz, Jean |
title |
Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor |
title_short |
Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor |
title_full |
Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor |
title_fullStr |
Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor |
title_full_unstemmed |
Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor |
title_sort |
nuclear hmgb1 protects from nonalcoholic fatty liver disease through negative regulation of liver x receptor |
publishDate |
2023 |
url |
https://hdl.handle.net/10356/164369 |
_version_ |
1759856262765346816 |