Peroxisome proliferator-activated receptor (PPAR)alpha is a nuclear receptor activated
by natural ligands such as fatty acids as well as by synthetic ligands such as fibrates
currently used to treat dyslipidemia. PPARalpha regulates the expression of genes
encoding proteins that are involved in lipid metabolism, fatty acid oxidation, and
glucose homeostasis, thereby improving markers for atherosclerosis and insulin resistance.
In addition, PPARalpha exerts anti-inflammatory effects both in the vascular wall
and the liver. Here we provide an overview of the mechanisms through which PPARalpha
affects the initiation and progression of atherosclerosis, with emphasis on the modulation
of atherosclerosis-associated inflammatory responses. PPARalpha activation interferes
with early steps in atherosclerosis by reducing leukocyte adhesion to activated endothelial
cells of the arterial vessel wall and inhibiting subsequent transendothelial leukocyte
migration. In later stages of atherosclerosis, evidence suggests activation of PPARalpha
inhibits the formation of macrophage foam cells by regulating expression of genes
involved in reverse cholesterol transport, formation of reactive oxygen species (ROS),
and associated lipoprotein oxidative modification among others. Furthermore, PPARalpha
may increase the stability of atherosclerotic plaques and limit plaque thrombogenicity.
These various effects may be linked to the generation of PPARalpha ligands by endogenous
mechanisms of lipoprotein metabolism. In spite of this dataset, other reports implicate
PPARalpha in responses such as hypertension and diabetic cardiomyopathy. Although
some clinical trials data with fibrates suggest that fibrates may decrease cardiovascular
events, other studies have been less clear, in terms of benefit. Independent of the
clinical effects of currently used drugs purported to achieve PPARalpha, extensive
data establish the importance of PPARalpha in the transcriptional regulation of lipid
metabolism, atherosclerosis, and inflammation.