Elevated levels of plasma homocysteine (Hey) are associated with increased risk of cardiovascular disease though it is uncertain whether increases in Hey represent a cause or a consequence of the disease process. Plasma Hey exists in reduced, free oxidized, and protein-bound forms, that together comprise total Hey (tHcy). Free reduced Hey is thought to be the atherogenic, though minor, sub-fraction of tHcy. Recent reports have indicated that fenofibrate and other fibrates are capable of moderately increasing plasma tHcy. As many of the effects of fibrates are known to be mediated by the nuclear receptor PPARalpha, we determined the effect of fenofibrate on tHcy in PPARalpha-deficient mice. We further examined the effect of fenofibrate and fenofibrate plus folate supplementation on total as well as protein-bound Hey in rats. Fenofibrate significantly increased serum tHcy in wild-type mice but not in PPARalpha deficient mice. In rats, fenofibrate increased serum tHcy by 69%, while the co-administration of folate with fenofibrate increased tHcy by only 7%. In spite of the above increase in tHcy in rats, only the protein-bound fraction of Hey was increased. In a further study, fenofibrate also induced a significant increase in tHcy, while in spite of this, ex vivo peroxidation of VLDL + LDL was beneficially lowered and the lag time prolonged. In summary, fenofibrate increases serum tHcy in rodents in a PPARalpha-dependent manner. The increase in rats is solely due to protein-bound Hey as atherogenic, reduced Hey was unchanged. While awaiting corroboration in human, our results suggest that the extent and mechanism of the increase in total Hey in patients treated with fenofibrate should not a priori be associated with relevant risk. (C) 2002 Elsevier Science (USA). All rights reserved.