Hepatic and intestinal tissue-specific <i>Fxr</i> 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 <i>Fxr</i> in both liver and intestine (<i>Fxr</i>^ΔL/ΔIN). Notably, <i>Fxr</i>^ΔL/ΔIN mice exhibited significantly increased BA levels in the serum and liver, which were consistent with <i>Fxr</i> whole body KO mice (<i>Fxr</i>^-/-). However, <i>Fxr</i>^ΔL mice only showed elevated hepatic BA concentration, whereas <i>Fxr</i>^ΔIN displayed remarkably increased BA concentration in feces. <i>Fxr</i> deletion increased the BA synthesis genes mRNA level, such as <i>Cyp7a1</i> and <i>Cyp8b1</i>, but reduced the expression of FXR downstream target genes <i>Shp</i> and <i>Fgf15</i>. 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.<b>NEW & NOTEWORTHY</b> We successfully developed a double tissue-specific <i>Fxr</i> 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. <i>Fxr</i>^ΔL/ΔIN mice exhibited significantly increased BA levels in the serum and liver, which were consistent with <i>Fxr</i>^-/- mice. We established a powerful tool for therapeutic strategies for bile acid metabolism disorders associated with FXR.