.-High-fructose consumption is associated with insulin resistance and diabetic dyslipidemia, but the underlying mechanism is unclear. We show in hamsters that highfructose feeding stimulated forkhead box O1 (FoxO1) production and promoted its nuclear redistribution in liver, correlating with augmented apolipoprotein C-III (apoC-III) production and impaired triglyceride metabolism. High-fructose feeding upregulated peroxisome proliferator-activated receptor-␥ coactivator-1 and sterol regulatory element binding protein-1c expression, accounting for increased fat infiltration in liver. High-fructose-fed hamsters developed hypertriglyceridemia, accompanied by hyperinsulinemia and glucose intolerance. These metabolic aberrations were reversible by fenofibrate, a commonly used anti-hypertriglyceridemia agent that is known to bind and activate peroxisome proliferator-activated receptor-␣ (PPAR␣). PPAR␣ physically interacted with, but functionally antagonized, FoxO1 in hepatic apoC-III expression. These data underscore the importance of FoxO1 deregulation in the pathogenesis of hypertriglyceridemia in high-fructose-fed hamsters. Counterregulation of hepatic FoxO1 activity by PPAR␣ constitutes an important mechanism by which fibrates act to curb apoC-III overproduction and ameliorate hypertriglyceridemia.hypertriglyceridemia; forkhead box O1; peroxisome proliferator-activated receptor-␣; apolipoprotein C-III; very-low-density lipoproteintriglyceride; microsomal triglyceride transfer protein HYPERTRIGLYCERIDEMIA IS CHARACTERIZED by increased production of very-low-density lipoprotein (VLDL) and/or decreased clearance of triglyceride (TG)-rich particles (4). Due to its proatherogenic profile, hypertriglyceridemia is a major contributing factor for the pathogenesis of atherosclerosis and coronary artery disease in obesity and type 2 diabetes. While the pathophysiology of hypertriglyceridemia is poorly understood, its close association with visceral adiposity and type 2 diabetes implicates insulin resistance as a causative factor in the development of hypertriglyceridemia (5,12,22,29,42). However, the molecular events that link insulin resistance to the pathogenesis of hypertriglyceridemia remain elusive.An important player in plasma VLDL-TG metabolism is apolipoprotein C-III (apoC-III). It functions as an inhibitor of lipoprotein lipase and hepatic lipase, playing a pivotal role in the hydrolysis and clearance of TG-rich particles such as VLDL-TG and chylomicrons (27,36,51,53). Elevated plasma apoC-III levels are associated with impaired clearance of TG-rich particles, leading to the accumulation of TG-rich lipoprotein remnants in plasma and the development of hypertriglyceridemia.Our recent data indicate that forkhead box O1 (FoxO1), a nuclear transcription factor known to be a mediator of insulin signaling, plays an important role in hepatic regulation of apoC-III. FoxO1 stimulates hepatic apoC-III expression, which is counteracted by insulin (2). Elevated FoxO1 production in liver augments hepatic apoC-III expression, r...