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Journal of Lipid Research, Vol. 47, 778-786, April 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Overexpression of estrogen receptor increases hepatic cholesterogenesis, leading to biliary hypersecretion in mice¹

Helen H. Wang, Nezam H. Afdhal and David Q-H. Wang²

Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, MA

¹ This paper was presented in part at the Annual Meeting of the American Gastroenterological Association, New Orleans, LA, in 2004, and published as an abstract (Gastroenterology 2004; 126: A673).

Published, JLR Papers in Press, December 27, 2005.

² To whom correspondence should be addressed. e-mail:dqwang{at}caregroup.harvard.edu

We explored whether there is an "estrogen-ER-SREBP-2" (for estrogen-estrogen receptor subtype -sterol-regulatory element binding protein-2) pathway for regulating hepatic cholesterol biosynthesis in ovariectomized AKR mice treated with 17ß-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. ER 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-ER-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.

Supplementary key words bile • bile flow • bile salt • biliary secretion • crystallization • liquid crystals • microscopy • cholesterol saturation index

Abbreviations: ER, estrogen receptor; ER, estrogen receptor subtype ; E₂, 17ß-estradiol; OVX, ovariectomized; SREBP-2, sterol-regulatory element binding protein-2

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