The transcription factor farnesoid X receptor (FXR) has recently been implicated in the control of hepatic triglyceride production. Activation of FXR may ameliorate hypertriglyceridemia, a cardinal feature of the metabolic syndrome. Since hamsters share many characteristic features of human lipid metabolism, we used a high fructose-fed hamster model to study the impact of FXR activation with chenodeoxycholic acid (CDCA) on plasma lipoprotein metabolism. Male Syrian hamsters fed a diet containing 60% kcal from fructose for 2 weeks developed hypertriglyceridemia and hypercholesterolemia (+121, and +60, p = 0.005 and 0.0004, when compared to controls) due to increased hepatic lipoprotein production. This could be largely attributed to enhanced hepatic de novo lipogenesis, as indicated by increased expression of sterol regulatory element binding protein 1 (Srebp 1), Fatty acid synthase (Fas) and steaoryl-CoA desaturase 1 (Scd-1). Lipoprotein analysis demonstrated that the increase in plasma triglycerides occurred in the VLDL density range whereas increases in VLDL, IDL/LDL and HDL cholesterol accounted for the elevated plasma cholesterol concentrations. Addition of 0.1% CDCA to the high fructose diet decreased hepatic de novo lipogenesis and consequently triglyceride production and prevented the increases in plasma triglycerides and cholesterol (-40, and -18 %, p=0.03 and 0.03, when compared to high fructose-fed animals). CDCA treated animals had lower VLDL triglycerides and decreased VLDL and IDL/LDL cholesterol plasma concentrations. These data demonstrate that activation of FXR with CDCA effectively lowers plasma triglyceride and cholesterol concentrations, mainly by decreasing de novo lipogenesis and hepatic secretion of triglyceride- rich lipoproteins. Our studies identify activators of the nuclear receptor FXR as promising new tools in the therapy of hypertriglyceridemic states, including the insulin resistance syndrome and type 2 diabetes.