Thus, a positive feedback loop may be created by hepatic sphingolipid accumulation to increase lipotoxicity-mediated sustained ER stress or maladaptive UPR that correlates with the sexual dimorphism of diet-induced development of steatosis and progression to NASH enhanced by Ormdl3 overexpression. This evidence concerns the gene ORMDL3 and metabolic dysfunction-associated steatohepatitis.