Peroxisome proliferator-activated receptors: new targets for the pharmacological modulation of macrophage gene expression and function

This review focuses on recent advances on the roles of peroxisome proliferator-activated receptors in the control of lipid metabolism, and the inflammatory response of macrophages and the potential participation of these actions in the modulation of atherogenesis. Altered macrophage functions contribute to the pathogenesis of many infectious, immunological and inflammatory disease processes. Pharmacological modulation of macrophage gene expression therefore represents an important strategy for the prevention and treatment of inflammation-related diseases, such as atherosclerosis. Peroxisome proliferator-activated receptors are lipid-activated transcription factors that control lipid and lipoprotein metabolism, glucose and energy homeostasis, as well as cellular differentiation and proliferation. Recent data suggest that peroxisome proliferator-activated receptor alpha and peroxisome proliferator-activated receptor gamma activators may decrease the incidence of cardiovascular disease, not only by correcting metabolic disorders, but also by directly acting at the level of the vascular wall. In this context, ligand-activated peroxisome proliferator-activated receptors control cellular functions by regulating gene expression in different cell types, including monocytes, macrophages and foam cells. These findings identify the crucial roles of peroxisome proliferator-activated receptors in macrophages, improving the comprehension of the patho-physiological mechanisms of atherogenesis. Moreover, a scientific rationale for the evaluation of peroxisome proliferator-activated receptor activators in the treatment of inflammatory disorders such as atherosclerosis is thus provided.