Abstract 5521: Activation of Farnesoid X Receptor (FXR) Reduces Atherosclerosis in LDLRKO and apoEKO Mice

The nuclear hormone receptors farnesoid X Receptor (FXR) and small heterodimer partner (SHP) regulate bile acid synthesis and cholesterol homeostasis in a complex fashion. In regard to atherosclerosis, FXR repression of bile acid synthesis has been proposed to be either detrimental due to reduced elimination of cholesterol or beneficial due to decreased cholesterol absorption. FXRKO mice have failed to resolved this question, with atherosclerotic lesions in FXRKO mice either enhanced (apoE, FXRdKO mice) or reduced (LDLR, FXRdKO mice). Here we demonstrate that the synthetic ligand FXR-450 blocked Western diet-mediated increases in VLDL and LDL cholesterol in both male or female LDLRKO and male or female apoEKO mice. Correspondingly, FXR-450 strongly reduced lesion development in female and male ApoEKO mice fed a Western diet. To determine if FXR-450 reduction of lipids and atherosclerotic lesion size is solely mediated by induction of SHP and repression of bile acid synthesis, LDLRKO/SHPKO and ApoEKO/SHPKO were similarly analyzed. In female LDLRKO/SHPKO or female apoEKO/SHPKO, FXR-450 no longer reduced VLDL or LDL cholesterol. Surprisingly, FXR-450 still reduced VLDL and LDL cholesterol in male LDLRKO/SHPKO and male apoEKO/SHPKO. Further FXR-450 significantly reduced lesion development in male apoEKO/SHPKO mice. These results demonstrate activation of FXR has highly beneficial effects on plasma lipids and lesion formation in multiple mouse atherosclerosis models. Further, while induction of SHP appears to be the predominant protective mechanism of FXR activation in female mice, additional mechanisms may play a role, particularly in male mice.