The role of farnesoid X receptor (FXR) in the development of atherosclerosis has been unclear. Here, LDL receptor (LDLR 2/2 ) or apolipoprotein E (apoE 2/2 ) female or male mice were fed a Western diet and treated with a potent synthetic FXR agonist, WAY-362450. Activation of FXR blocked diet-induced hypertriglyceridemia and elevations of non-HDL cholesterol and produced a near complete inhibition of aortic lesion formation. WAY-362450 also induced small heterodimer partner (SHP) expression and repressed cholesterol 7a-hydroxylase (CYP7A1) and sterol 12 a-hydroxylase (CYP8B1) expression. To determine if SHP was essential for these protective activities, LDLR Farnesoid X receptor (FXR) is a nuclear hormone receptor critically involved in the regulation of bile acid homeostasis. It is now recognized that bile acids serve as the natural ligands for FXR (1). Once activated, FXR in turn induces the expression of another nuclear hormone receptor, small heterodimer partner (SHP). SHP does not contain a DNA binding domain, but functions as a transcriptional repressor by interacting with other transcription factors bound to DNA. In bile acid metabolism, SHP functions to repress activity of LRH-1 and HNF4 (2-6). These two factors drive expression of cholesterol 7a-hydroxylase (CYP7A1) and sterol 12 a-hydroxylase (CYP8B1), the two enzymes controlling the bile acid pool size and the hydrophobicity of the bile acid pool (7,8). In this manner, a classical negative feedback pathway is established in which bile acids regulate their own synthesis.In regard to lipid metabolism, the FXR activation by either bile acid ligands or potent synthetic ligands has been shown to consistently decrease plasma triglyceride (TG) levels. Multiple mechanisms are involved in this process, including control of lipoprotein lipase activity by FXR-induced stimulation of apoCII expression (9) and repression of apoCIII expression (10), as well as decreased production of VLDL due to diminished SREBP-1c activity and TG synthesis in the liver (11). In regard to cholesterol metabolism, a more complex picture has emerged. A major pathway for elimination of cholesterol from the body is conversion of cholesterol into bile acids. FXR repression of CYP7A1 expression might thus be predicted to increase dyslipidemia and atherosclerosis. Furthermore, FXR can repress apoAI expression and decrease HDL cholesterol levels (12), another potential detrimental effect. Conversely, bile acids are essential for cholesterol absorption (8), and inhibition of cholesterol absorption by ezetimibe strongly decreases plasma LDL cholesterol levels and atherosclerosis (13). Thus, activation of FXR could theoretically have either beneficial effects or negative effects on plasma cholesterol levels and atherosclerosis. Abbreviations: apoE, apolipoprotein E; BSEP, bile salt export protein; CYP7A1, cholesterol 7a-hydroxylase; CYP8B1, sterol 12 a-hydroxylase; FXR, farnesoid X receptor; IBABP, ileal bile acid binding protein; LDLR, low density lipoprotein receptor; LXR, liver X re...