Hepatic and intestinal tissue-specific Fxr deficiency alters bile acid homeostasis in female mice

Farnesoid X receptor (FXR), predominantly expressed in the liver and intestine, plays a crucial role in regulating bile acid (BA) metabolism. However, the specific contributions of FXR in different tissues to BA homeostasis remain unclear. To elucidate the comprehensive roles of FXR, we developed a novel double tissue-specific knockout (KO) mouse model of Fxr in both liver and intestine (Fxr^ΔL/ΔIN). Notably, Fxr^ΔL/ΔIN mice exhibited significantly increased BA levels in the serum and liver, which were consistent with Fxr whole body KO mice (Fxr^-/-). However, Fxr^ΔL mice only showed elevated hepatic BA concentration, whereas Fxr^ΔIN displayed remarkably increased BA concentration in feces. Fxr deletion increased the BA synthesis genes mRNA level, such as Cyp7a1 and Cyp8b1, but reduced the expression of FXR downstream target genes Shp and Fgf15. These findings provide a valuable model to underscore the pivotal functions of tissue-specific FXR in maintaining BA homeostasis. Moreover, these insights facilitate the development of FXR-targeted therapeutic strategies for the BA dysregulation disease treatment.NEW & NOTEWORTHY We successfully developed a double tissue-specific Fxr knockout (DKO) mouse model, which provides a novel tool for investigation of FXR functions in the liver and intestine. Unlike whole body KO, the DKO model excludes the FXR impact on other tissues. Fxr^ΔL/ΔIN mice exhibited significantly increased BA levels in the serum and liver, which were consistent with Fxr^-/- mice. We established a powerful tool for therapeutic strategies for bile acid metabolism disorders associated with FXR.