Shown are signaling pathways that repress transcription of the gene encoding CYP7A1, the rate-limiting enzyme in bile acid synthesis. Established pathways for the repression of Cyp7a1 in mice are indicated by solid lines. These include JNK and the nuclear bile acid receptor FXR. Activation of FXR represses CYP7A1 by induction of the orphan nuclear receptor SHP and FGF19, which acts through FGFR4. Activation of the nuclear receptors pregnane X receptor (PXR) and PPARα by xenobiotics and fatty acids, respectively, also represses CYP7A1 through unknown mechanisms. Speculative pathways are shown as dotted lines. In this issue, Ito and colleagues show that mice lacking βKlotho have increased Cyp7a1 expression and bile acid synthesis and are resistant to the formation of gallstones (2). The similar phenotypes of βKlotho-KO and FGFR4-KO mice (8), including increased bile acid synthesis and small gallbladders, suggest that these proteins may act through a common pathway.