FIGURE 2.

FOXA2 and BA homeostasis. In the liver, FOXA2 directly regulates the expression of genes of transporters Oatp2 and Mrp2 involved in BA transport and, indirectly, Cyp3a11. Deficiency of FOXA2, as seen in cholestatic patients, has decreased the gene expression of Oatp2, Mrp2 (along with Mrp3 and Mrp4, not shown), and Cyp3a11, contributing to cholestasis and increased BA accumulation within the liver. Excess BAs activate FXR, which in turn induces gene expression of Shp to suppress the expression of genes encoding rate-limiting enzymes for BA synthesis, Cyp7a1 and Cyp8b1, to mitigate cholestasis and excess BAs in the liver. FOXA2 is also believed to bind alongside FXR in the upstream regulatory region to elicit these effects. Abbreviations: BA, bile acid; FXR, farnesoid X receptor.