Here, we unveiled the important role of HMGB1 in the repressive effect of the LXRα/PPARγ axis, during metabolic stress, as demonstrated by increased liver steatosis in hepatocyte-specific Hmgb1 knockout (HMGB1ΔHep) mice and a reduced hepatic lipid load in Hmgb1-overexpressing mice when subjected to nutritional stress. This evidence concerns the gene NR1H3 and fatty liver disease.