Men and postmenopausal women are more prone to developing non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) than premenopausal women. However, the pathological links and underlying mechanisms of this disparity are still elusive. The sex-difference in hepatic very low-density lipoprotein (VLDL) assembly and secretion may contribute to NAFLD development. Estrogen-related receptor alpha (ERRĪ±) is a key regulator of several metabolic processes. We hypothesized that ERRĪ± plays a role contributing to the sex-difference in hepatic VLDL assembly and secretion.VLDL secretion and essential genes governing said process were assessed in male and female mice. Liver-specific ERRĪ±-deficient (ERRĪ±LKO) mice were generated to assess the rate of hepatic VLDL secretion and alteration in target gene expression. Overexpression of either microsomal triglyceride transfer protein () or phospholipase A2 G12B () by adenovirus was performed to test if the fatty liver phenotype in male ERRĪ±LKO mice was due to defects in hepatic VLDL secretion. Female ERRĪ±LKO mice were put on a diet high in saturated fat, fructose and cholesterol (HFHC) to promote NASH development. Wild type female mice were either ovariectomized or treated with tamoxifen to induce a state of estrogen deficiency or disruption in estrogen signaling. Adenovirus was used to overexpress ERRĪ± in these mice to test if ERRĪ± was sufficient to rescue the suppressed VLDL secretion due to estrogen dysfunction. Finally, wild type male mice on a high-fat diet (HFD) were treated with an ERRĪ± inverse agonist to assess if suppressing ERRĪ± activity pharmacologically would lead to fatty liver development.ERRĪ± is an indispensable mediator modulating hepatic triglyceride-rich very low-density lipoprotein (VLDL-TG) assembly and secretion through coordinately controlling target genes apolipoprotein B (),andin a sex-different manner. Hepatic VLDL-TG secretion is blunted in ERRĪ±LKO mice, leading to hepatosteatosis which exacerbates endoplasmic reticulum stress and inflammation paving ways for NASH development. Importantly, ERRĪ± acts downstream of estrogen/ERĪ± signaling in contributing to the sex-difference in hepatic VLDL secretion effecting hepatic lipid homeostasis.Our results highlight ERRĪ± as a key mediator which contributes to the sex disparity in NAFLD development, suggesting that selectively restoring ERRĪ± activity in the liver may be a novel strategy for treating NAFLD/NASH. Rationale: Methods: Results: Conclusions: Mttp Pla2g12b Apob Mttp Pla2g12b
