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

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


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.