Nuclear HMGB1 protects from non-alcoholic fatty liver diseases through negative regulation of liver X receptor
Year: 2021
Type: preprint
Abstract: Dysregulations of lipid metabolism in the liver may trigger steatosis progression leading to potentially severe clinical consequences such as non-alcoholic fatty liver diseases (NAFLD). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and the activity of multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis during metabolic stress in NAFLD. Mice with liver-specific Hmgb1 -deficiency display exacerbated liver steatosis and hepatic insulin resistance when subjected to a high-fat diet or after fasting/refeeding. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXRα activity resulting in increased lipogenesis. HMGB1 repression is not mediated through nucleosome landscape re-organization but rather via a preferential DNA occupation in region carrying genes regulated by LXRα. Together these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target LXRα axis during NAFLD.
Authors: Jean Personnaz, Enzo Piccolo, Alizée Dortignac, Jason S. Iacovoni, Jérôme Mariette, Arnaud Polizzi, Aurélie Batut, Simon Deleruyelle, Romain Paccoud, Elsa Moreau, Frédéric Martins, Thomas Clouaire, Fadila Benhamed, Alexandra Montagner, Walter A. Wahli, Robert F. Schwabe, Armelle Yart, Isabelle Castan-Laurell, Catherine Postic, Cédric Moro, Gaelle Legube, Chih-Hao Lee, Hervé Guillou, Philippe Valet, Cédric Dray, Jean-Philippe Pradère
Institutions: Centre National de la Recherche Scientifique, Université Toulouse III - Paul Sabatier, Inserm, Institut des Maladies Métaboliques et Cardiovasculaires, RESTORE, Université de Toulouse, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Mathématiques et Informatique Appliquées Toulouse, École Nationale Vétérinaire de Toulouse, Toxicologie Alimentaire, Genotoul coordination, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Centre de Biologie Intégrative de Toulouse, Université Paris Cité, Institut Cochin, Nanyang Technological University, University of Lausanne, Columbia University, Harvard University
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3130575671