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 acids (BAs) metabolism. However, the specific contributions of FXR in different tissues to BAs homeostasis remain unclear. To elucidate the comprehensive roles of FXR, we developed a novel double tissue-specific knockout (KO) mice 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, FxrΔL mice only showed elevated hepatic BAs concentration, while FxrΔIN displayed remarkably increased BA concentration in feces. Fxr deletion increased the BAs 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 BAs homeostasis. Moreover, these insights facilitate the development of FXR-targeted therapeutic strategies for the BAs dysregulation disease treatment.