The proposed model underlying the potential lithogenic mechanisms of estrogen through the estrogen receptor 1 (ESR1) pathway in the liver

The proposed model underlying the potential lithogenic mechanisms of estrogen through the estrogen receptor 1 (ESR1) pathway in the liver. In the liver there is a possible “estrogen-ESR1-SREBP-2” pathway promoting cholesterol biosynthesis and hepatic secretion of biliary cholesterol. The negative feedback regulation of cholesterol biosynthesis (as shown in a dashed line) is inhibited by ESR1 that is activated by estrogen, mostly through stimulating the activity of sterol regulatory element-binding protein-2 (SREBP-2) with the resulting activation of the SREBP-2 responsive genes for the cholesterol biosynthetic pathway. Consequently, these alterations induce excess secretion of newly synthesized cholesterol and supersaturation of bile that predisposes to cholesterol precipitation and gallstone formation. Moreover, the hepatic ESR1 activated by estrogen could stimulate the activity of ATP-binding cassette (ABC) transporter ABCG5 and ABCG8 on the canalicular membrane of the hepatocyte and promote biliary cholesterol secretion. Of special note is that these lithogenic effects of estrogen are inhibited by the antiestrogenic ICI 182,780. In addition, the estrogen effects on increasing cholesterol biosynthesis and promoting cholesterol gallstone formation are, in part, blocked by deletion of the Esr1 gene. See text for details. Modified from Reference [], with permission.

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New insights into the molecular mechanisms underlying effects of estrogen on cholesterol gallstone formation. () Helen H. Wang, et al. Biochim Biophys Acta. ;1791(11):1037-1047. Figure: F4. All organisms Rattus norvegicus Mus musculus Cricetulus griseus Homo sapiens Cavia porcellus Arabidopsis thaliana

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