Several studies demonstrated that a significant activation of PXR in mice fed with a diet rich in fat and cholesterol promoted the typical hallmarks of NAFLD and NASH, such as steatosis, inflammation, and lipotoxicity, suggesting that PXR activation seems to increase lipid accumulation in the liver, promoting a “fatty phenotype” [63,64,65]. This evidence concerns the gene NR1I2 and metabolic dysfunction-associated steatotic liver disease.