SAT009 Investigating The Role Of Hepatic Small Heterodimer Partner In Regulating Gallstone Formation

Disclosure: N.M. Dang: None. S. Anakk: None. Nuclear receptor, Small Heterodimer partner (Shp) regulates bile acid homeostasis by inhibiting transcription of Cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme involved in converting cholesterol to bile acids, within the liver. Bile acid regulation prevents the formation of gallstones as cholesterol is excreted into bile along with bile acids and phospholipids. How hepatic Shp affects the development of gallstones and the mechanisms underlying these effects remain unclear. Here we used a liver-specific knockout mouse model and a lithogenic diet model to uncover potential liver-to-gallbladder crosstalk that contributes to gallstone development. Previously, we had shown that the knockout of Shp alters bile acid composition, resulting in higher percentages of secondary bile acid, deoxycholic acid. This increased the hydrophobic index of hepatic bile acids and also implicated a trend for a subsequent increase in the hydrophobicity of biliary bile. Higher hydrophobicity is sufficient to increase susceptibility to developing gallstones by promoting cholesterol nucleation. Of note, the expression of transporter genes Abcg5 and Aqp1 were altered in the gallbladder of hepatic Shp knockout mice, indicating a potential change in their bile composition. The enterokine, Fgf15 is known to stimulate gallbladder filling through its interaction with its receptor, Fgfr4. Recently, the Fgf15-Fgfr4 axis was shown to prevent degradation of the SHP protein such that impeding this axis led to higher Cyp7a1 transcript, increased bile acid levels, and altered gallbladder filling. Taken together, these findings suggest that hepatic Shp acts as a central node that regulates bile acid transport, homeostasis, and composition within the gall bladder and thus can prevent gallstone development. Elucidating Shp-mediated liver-to-gallbladder crosstalk is important for understanding the contribution of liver dysfunction towards gallbladder diseases and gallstones. Presentation: Saturday, June 17, 2023