PT  - JOURNAL ARTICLE
AU  - Jean Personnaz
AU  - Enzo Piccolo
AU  - Alizée Dortignac
AU  - Jason S. Iacovoni
AU  - Jérôme Mariette
AU  - Arnaud Polizzi
AU  - Aurélie Batut
AU  - Simon Deleruyelle
AU  - Romain Paccoud
AU  - Elsa Moreau
AU  - Frédéric Martins
AU  - Thomas Clouaire
AU  - Fadila Benhamed
AU  - Alexandra Montagner
AU  - Walter A. Wahli
AU  - Robert F. Schwabe
AU  - Armelle Yart
AU  - Isabelle Castan-Laurell
AU  - Catherine Postic
AU  - Cédric Moro
AU  - Gaelle Legube
AU  - Chih-Hao Lee
AU  - Hervé Guillou
AU  - Philippe Valet
AU  - Cédric Dray
AU  - Jean-Philippe Pradère
TI  - Nuclear HMGB1 protects from non-alcoholic fatty liver diseases through negative regulation of liver X receptor
AID  - 10.1101/2021.02.17.431446
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.02.17.431446
4099  - http://biorxiv.org/content/early/2021/02/17/2021.02.17.431446.short
4100  - http://biorxiv.org/content/early/2021/02/17/2021.02.17.431446.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.