The recently discovered APOA5 gene has been shown in humans and mice to be important in determining plasma triglyceride levels, a major cardiovascular disease risk factor. apoAV represents the first described apolipoprotein where overexpression lowers triglyceride levels. Since fibrates represent a commonly used therapy for lowering plasma triglycerides in humans, we investigated their ability to modulate APOA5 gene expression and consequently influence plasma triglyceride levels. Human primary hepatocytes treated with Wy 14,643 or fenofibrate displayed a strong induction of APOA5 mRNA. Deletion and mutagenesis analyses of the proximal APOA5 promoter firmly demonstrate the presence of a functional peroxisome proliferator-activated receptor response element. These findings demonstrate that APOA5 is a highly responsive peroxisome proliferator-activated receptor ␣ target gene and support its role as a major mediator for how fibrates reduce plasma triglycerides in humans.Coronary heart disease continues to be a major cause of morbidity and mortality worldwide. Several epidemiological studies established that, in addition to elevated low density lipoprotein and reduced high density lipoprotein level, elevated triglycerides (TGs) 1 constitute an independent risk factor for coronary heart disease (1, 2). In addition, hypertriglyceridemia is often associated with the metabolic syndrome that characterizes diabetes and obesity (3, 4). Therefore, the identification of factors or genes affecting triglyceride metabolism is of significant medical importance for the correction of hypertriglyceridemia and associated coronary heart disease.Apolipoproteins play a determinant role in lipoprotein metabolism and in lipid homeostasis. More specifically, the APOA1/C3/A4 apolipoprotein gene cluster is tightly linked to plasma lipid profiles. Indeed, mutations in members of this cluster have been shown to cause severe dyslipidemia and heightened atherosclerosis susceptibility (5-8). A comparative genomic characterization of the APOA1/C3/A4 gene cluster flanking regions led to the recent identification of a new apolipoprotein gene, apolipoprotein A5 (APOA5), present in both mice and humans (9). apoAV shares homology with several apolipoproteins, most prominently apoAIV, and is 368 and 366 amino acids long in mice and human, respectively. This gene appears to be predominantly expressed in the liver and resides on high density lipoprotein and very low density lipoprotein particles (9, 10).The properties of apoAV were investigated by creating human APOA5 transgenic and knock-out mice and by searching for associations between human APOA5 polymorphisms and plasma lipid parameters. The Apoa5 knock-out mice display a 400% increase in plasma triglycerides compared with wild-type mice, while APOA5 transgenics exhibit triglyceride levels corresponding to one-third of those in control mice. This determinant link between APOA5 and triglycerides was supported in several separate human studies through the consistent demonstration of associations betwe...