Notably, hepatic dysregulation of glucose and lipid homeostasis are hallmarks of human non-alcoholic fatty liver disease (NAFLD)25,26, and here, we show that hepatic ablation of Xbp1 disrupts the 12-h clock, negatively impacts indices of metabolic fitness, and promotes a defined NAFLD phenotype. Here, CLOCK is linked to metabolic dysfunction-associated steatotic liver disease.