Characterization of Novel Low Bile Acid Mouse Model

Bile acids (BAs) are signaling molecules synthesized in the liver initiated by CYP7A1 and CYP27A1 in the classical and alternative pathways, respectively. BAs are essential for cholesterol clearance, intestinal absorption of lipids, and endogenous modulators of farnesoid x receptor (FXR). FXR is critical in maintaining BA homeostasis and gut-liver crosstalk. Complex reactions in vivo and the lack of suitable animal models impede on our understanding of the functions of individual BAs. In the study, we characterized the low in vivo BA mouse model comparing naive WT and DKO (Cyp7a1-/-/Cyp27a1-/-, DKO) mice. In the same study we also investigated the effects of three-day feeding of cholic acid (CA), deoxycholic acid (DCA), or ursodeoxycholic acid (UDCA) in a novel low BA mouse model. The current study is the first to mechanistically investigate to what degree that CA, DCA and UDCA signal individually in a low-BA mouse model at physiological/non-hepatotoxic concentrations. We determined BA signaling by the FXR-fibroblast growth factor 15 axis, liver injury, and BA levels and composition. Low BAs in DKO mice was associated with higher basal inflammation and altered lipid metabolism compared to WT mice. Dietary CA/DCA altered tissue BA profiles similarly. UDCA did not offer any overt protective effects and altered tissue BA profile compared to baseline. Our data demonstrate that CA, DCA and UDCA feeding activates FXR with tissue specificity. UDCA promoted a more hydrophobic tissue BA pool with the profiles shifted towards non-12-alpha-OH BAs and secondary BAs. These findings allow us to determine more precisely the individual effect of BAs in vivo on BA-FXR signaling and overall BA homeostasis, which may help to better understand the mechanisms by which BAs signal in liver physiology and pathologies.