FIG. 7.

Working model for a possible G-1–GPR30–CYP7A1 pathway enhancing cholelithogenesis. We found that the GPR30-selective agonist G-1 activates hepatic Gpr30 expression, with the latter suppressing activity of Cyp7a1, the rate-limiting enzyme for the classical pathway of bile salt synthesis. As a result, these changes lead to increased biliary cholesterol concentration and hepatic bile salt hyposecretion, thereby reducing cholesterol solubility in bile and causing cholesterol-supersaturated bile that predisposes to solid cholesterol crystal precipitation and gallstone formation. Abbreviations: BS, bile salts; Ch, cholesterol; PL, phospholipids.