Sci Adv.: co-auth.: W.Wahli

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Sci Adv. 2022 Mar 25;8(12):eabg9055. doi: 10.1126/sciadv.abg9055. Epub 2022 Mar 25.

Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor

Jean Personnaz 1 2, Enzo Piccolo 1 2, Alizée Dortignac 1 2, Jason S Iacovoni 2, Jérôme Mariette 3, Vincent Rocher 4, Arnaud Polizzi 5, Aurélie Batut 2, Simon Deleruyelle 2, Lucas Bourdens 1, Océane Delos 2 6, Lucie Combes-Soia 7, Romain Paccoud 2, Elsa Moreau 2, Frédéric Martins 2 8, Thomas Clouaire 4, Fadila Benhamed 9, Alexandra Montagner 2, Walter Wahli 4 10 11, Robert F Schwabe 12, Armelle Yart 1 2, Isabelle Castan-Laurell 1 2, Justine Bertrand-Michel 2 6, Odile Burlet-Schiltz 7, Catherine Postic 9, Pierre-Damien Denechaud 2, Cédric Moro 2, Gaelle Legube 4, Chih-Hao Lee 13, Hervé Guillou 5, Philippe Valet 1 2, Cédric Dray 1 2, Jean-Philippe Pradère 1 2

Abstract

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.