Our results demonstrated that ERRα is an indispensable mediator required for estrogen/ERα signaling modulating hepatic VLDL secretion through coordinately controlling target genes Apob, Mttp and Pla2g12b. The imbalance of ERRα-mediated VLDL secretion leading to hepatic lipid accumulation may render female more prone to developing NAFLD/NASH under certain pharmacological or pathophysiological conditions including SERM treatment and estrogen deficiency. Here, ESR1 is linked to metabolic dysfunction-associated steatohepatitis.