Hepatic estrogen receptor α improves hepatosteatosis through upregulation of small heterodimer partner

Abstract

Background & aims: Estrogen participates in the control of energy homeostasis and lipid metabolism. However the role of hepatic estrogen receptor α (ERα) in triglyceride (TG) homeostasis remains poorly understood. This study aims to investigate the roles of estrogen and ERα in the regulation of hepatic TG metabolism.

Methods: Liver TG metabolism was analyzed in female mice with ovariectomy or tamoxifen treatment, and in hepatic ERα knockdown or overexpression. Phenotypes and expression of genes were compared in male and female mice with farnesoid X receptor deficiency. The mechanism of ERα in the regulation of small heterodimer partner (SHP) expression was further investigated.

Results: Female mice receiving ovariectomy or tamoxifen treatment exhibited hepatic TG accumulation. Ablation of ERα using adenoviral shRNA markedly increased hepatic TG accumulation, while overexpression of ERα ameliorated hepatosteatosis in obese mice. At the molecular level, estrogen upregulated hepatic SHP expression through binding to its proximal promoter. In addition, the roles of estrogen were largely blunted in mice with SHP deficiency.

Conclusion: These findings reveal a novel role of estrogen in improving hepatosteatosis through upregulation of SHP expression.

Keywords: ERα; Estrogen; FXR; Hepatosteatosis; SHP.