Metabolic benefits of 17 & alpha;-estradiol in liver are partially mediated by ER & beta; in male mice

Metabolic dysfunction underlies several chronic diseases. Dietary interventions can reverse metabolic declines and slow aging but remaining compliant is difficult. 17 & alpha;-estradiol (17 & alpha;-E2) treatment improves metabolic parameters and slows aging in male mice without inducing significant feminization. We recently reported that estrogen receptor & alpha; is required for the majority of 17 & alpha;-E2-mediated benefits in male mice, but that 17 & alpha;-E2 also attenuates fibrogenesis in liver, which is regulated by estrogen receptor & beta; (ER & beta;)-expressing hepatic stellate cells (HSC). The current studies sought to determine if 17 & alpha;-E2-mediated benefits on systemic and hepatic metabolism are ER & beta;-dependent. We found that 17 & alpha;-E2 treatment reversed obesity and related systemic metabolic sequela in both male and female mice, but this was partially blocked in female, but not male, ER & beta;KO mice. ER & beta; ablation in male mice attenuated 17 & alpha;-E2-mediated benefits on hepatic stearoyl-coenyzme A desaturase 1 (SCD1) and transforming growth factor & beta;1 (TGF-& beta;1) production, which play critical roles in HSC activation and liver fibrosis. We also found that 17 & alpha;-E2 treatment suppresses SCD1 production in cultured hepatocytes and hepatic stellate cells, indicating that 17 & alpha;-E2 directly signals in both cell-types to suppress drivers of steatosis and fibrosis. We conclude that ER & beta; partially controls 17 & alpha;-E2-mediated benefits on systemic metabolic regulation in female, but not male, mice, and that 17 & alpha;-E2 likely signals through ER & beta; in HSCs to attenuate pro-fibrotic mechanisms.