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

• Published in: Science advances Vol. 8; no. 12; p. eabg9055
• Main Authors: 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: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science (AAAS) 25-03-2022; American Association for the Advancement of Science
• Subjects: Biomedicine and Life Sciences; Diseases and Disorders; Health and Medicine; Life Sciences; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abg9055

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
deficiency display exacerbated liver steatosis, while
-overexpressing mice exhibited a protection from fatty liver progression when subjected to nutritional stress. Global transcriptome and functional analysis revealed that the deletion of
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.