出版社：American Society for Biochemistry and Molecular Biology
摘要：We explored whether there is an "estrogen-ER-SREBP-2" (for estrogen-estrogenreceptor subtype -sterol-regulatory element binding protein-2)pathway for regulating hepatic cholesterol biosynthesis in ovariectomizedAKR mice treated with 17ß-estradial (E2) at 6 µg/dayor E2 plus the antiestrogenic agent ICI 182,780 at 125 µg/dayand on chow or fed a high-cholesterol (1%) diet for 14 days.To monitor changes in cholesterol biosynthesis and newly synthesizedcholesterol secreted into bile, incorporation into digitonin-precipitablesterols in mice treated with 25 mCi of [3H]water was measuredin extracts of liver and extrahepatic organs 1 h later and inhepatic biles 6 h later. ER upregulated SREBP-2, with resultingactivation of SREBP-2-responsive genes in the cholesterol biosyntheticpathway. The E2-treated mice continued to synthesize cholesterolin spite of its excess availability from high dietary cholesterol,which reflects a loss in controlling the negative feedback regulationof cholesterol synthesis. These alterations augmented biliarycholesterol secretion and enhanced the lithogenicity of bile.However, these lithogenic effects of E2 were fully blocked byICI 182,780. We conclude that during estrogen treatment, morenewly synthesized cholesterol determined by the estrogen-ER-SREBP-2pathway is secreted into bile, leading to biliary cholesterolhypersecretion. These studies provide insights into therapeuticapproaches 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
-SREBP-2" (for estrogen-estrogen receptor subtype 
