Overexpression of estrogen receptor α increases hepatic cholesterogenesis, leading to biliary hypersecretion in mice

We explored whether there is an "estrogen-ERα-SREBP-2" (for estrogen-estrogen receptor subtype α-sterol-regulatory element binding protein-2) pathway for regulating hepatic cholesterol biosynthesis in ovariectomized AKR mice treated with 17β-estradial (E₂) at 6 μg/day or E₂ plus the antiestrogenic agent ICI 182,780 at 125 μg/day and on chow or fed a high-cholesterol (1%) diet for 14 days. To monitor changes in cholesterol biosynthesis and newly synthesized cholesterol secreted into bile, incorporation into digitonin-precipitable sterols in mice treated with 25 mCi of [³H]water was measured in extracts of liver and extrahepatic organs 1 h later and in hepatic biles 6 h later. ERα upregulated SREBP-2, with resulting activation of SREBP-2-responsive genes in the cholesterol biosynthetic pathway. The E₂-treated mice continued to synthesize cholesterol in spite of its excess availability from high dietary cholesterol, which reflects a loss in controlling the negative feedback regulation of cholesterol synthesis. These alterations augmented biliary cholesterol secretion and enhanced the lithogenicity of bile. However, these lithogenic effects of E₂ were fully blocked by ICI 182,780. We conclude that during estrogen treatment, more newly synthesized cholesterol determined by the estrogen-ERα-SREBP-2 pathway is secreted into bile, leading to biliary cholesterol hypersecretion. These studies provide insights into therapeutic approaches to cholesterol gallstones in high-risk subjects, especially those exposed to high levels of estrogen.