Plasma homocysteine levels increase in humans treated with fibrates but the molecular mechanisms are unknown. The goal of the present study was to determine the mechanism of this increase using animal models. Firstly, an increase in homocysteine was observed in mice treated with fenofibrate irrespective of the genetic background C57BL/6 or SV129. Secondly, as the effect of fenofibrate on gene expression is mediated through activation of the peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor belonging to the nuclear receptor family, it was determined whether the effect of fenofibrate on homocysteine levels were modulated through PPARα activation. Using PPARα-deficient mice, it was shown that the homocysteine increase after fenofibrate treatment was completely abolished in these animals. It can be concluded that fibrates increase homocystinemia through a PPARα-mediated mechanism and that mice constitute an animal model for analyzing the molecular mechanisms behind the homocysteine increase after fibrate therapy in dyslipidemic patients.
Fibrates constitute a class of frequently used normolipidemic drugs that effectively decrease triglyceride-rich lipoprotein and low-density lipoprotein and increase high-density lipoprotein (HDL) plasma levels in humans. They exert their effects, at least in part, through alterations in the transcription of genes encoding for proteins that control lipoprotein metabolism. 1 Indeed, fibrates activate specific transcription factors termed peroxisome proliferator-activated receptors (PPARs), a subfamily of nuclear receptors. 2 Particularly, the PPARα form mediates fibrate action on a number of genes involved in lipoprotein metabolism, fatty acid metabolism, and inflammation in the vascular wall. 1
Homocysteine is an intermediate compound formed during metabolism of methionine. It depends on a number of enzymes involved in the methionine cycle, folate cycle, and transsulfuration pathway. Folic acid, vitamin B6, and vitamin B12 serve as cofactors for a number of these enzymes. 3
Besides the effect on lipids, fenofibrate and bezafibrate were reported to increase plasma homocysteine concentrations in dyslipidemic patients in non-randomized, non-controlled clinical trials. 4–7 Among fibrates, only gemfibrozil has been demonstrated to increase homocysteine levels in a randomized controlled trial. 8 The mechanism of homocysteine increase in patients treated with fibrates remains to be established. Since fibrates induce the expression of several genes through PPARα activation, the aim of the present study was to investigate the role of PPARα in the fenofibrate-induced increase in homocysteine levels. To this end, we studied PPARα wild type (PPARα +/+) and homozygous-deficient mice (PPARα −/−).