Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor - INRAE - Institut national de recherche pour l’agriculture, l’alimentation et l’environnement Access content directly
Journal Articles Science Advances Year : 2022

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

Fadila Benhamed
Robert F. Schwabe
Catherine Postic
  • Function : Author
Chih-Hao Lee
Hervé Guillou

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.
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hal-03624265 , version 1 (30-03-2022)

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Jean Personnaz, Enzo Piccolo, Alizée Dortignac, Jason Iacovoni, Jérôme J. Mariette, et al.. Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor. Science Advances , 2022, 8 (12), ⟨10.1126/sciadv.abg9055⟩. ⟨hal-03624265⟩
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