Submitted on October 17, 2005
Revised on December 14, 2005
Accepted on December 27, 2005
Overexpression of estrogen receptor 
increases hepatic cholesterogenesis leading to biliary hypersecretion in mice
Helen H. Wang, Nezam H. Afdhal, and David Q-H Wang
Department of Medicine, Gastroenterology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
Corresponding Author: dqwang{at}caregroup.harvard.edu
We explored whether there is an “estrogen-ERa-SREBP-2” pathway for regulating hepatic cholesterol biosynthesis in ovariectomized AKR mice treated with 17b-estrodial (E2) at 6 mg/day or E2 plus the antiestrogenic ICI182,780 (125 mg/day), and on chow or fed a high (1%) cholesterol diet for 14 days. To monitor changes in cholesterol biosynthesis and newly-synthesized cholesterol secreted into bile, the incorporation into digitonin-precipitable sterols in mice treated with 25 mCi of [3H]water was measured in extracts of liver and extrahepatic organs 1 hour later and in hepatic biles 6 hours later. ERa up-regulated 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 ICI182,780. We conclude that during estrogen treatment, more newly-synthesized cholesterol determined by the estrogen-ERa-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 being exposed to high levels of estrogen.
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