Metabolic benefits of 17α-estradiol in liver are partially mediated by ERβ in male mice

Abstract

Metabolic dysfunction underlies several chronic diseases. Dietary interventions can reverse metabolic declines and slow aging but remaining compliant is difficult. 17-estradiol (17-E2) treatment improves metabolic parameters and slows aging in male mice without inducing significant feminization. We recently reported that estrogen receptor is required for the majority of 17-E2-mediated benefits in male mice, but that 17-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-E2-mediated benefits on systemic and hepatic metabolism are ER{beta}-dependent. We found that 17-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-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-E2 treatment suppresses SCD1 production in cultured hepatocytes and hepatic stellate cells, indicating that 17-E2 directly signals in both cell-types to suppress drivers of steatosis and fibrosis. We conclude that ER{beta} partially controls 17-E2-mediated benefits on systemic metabolic regulation in female, but not male, mice, and that 17-E2 likely signals through ER{beta} in HSCs to attenuate pro-fibrotic mechanisms.