Identification of Target Genes for Retinoid-related Orphan Receptors Involved in the Suppression of Atherosclerosis

Abstract

Retinoid-related orphan receptor alpha (RORα) participates in regulating several physiological processes, including metabolism and circadian rhythms. RORα is an important regulator of plasma cholesterol levels and is involved in lipid homeostasis. Its activation increases high-density lipoprotein (HDL) levels and metabolism of oxysterols. RORα-deficient mice develop atherosclerosis owing to decreased plasma HDL levels, increased expression of inflammatory cytokines, and ischemia/ reperfusion-induced damage. The transcriptional activity of RORα is controlled by cholesterol and its derivatives, endogenous ligands that form transcription initiation complexes. Conversely, when intracellular cholesterol is reduced by lipid-lowering drugs such as statins, which inhibit cholesterol synthesis, the transcriptional activity of RORα is attenuated. Therefore, studies have focused on identifying target genes regulated by RORα involved in alleviating atherosclerosis to develop new therapies. Characterization of ligands, transcription-mediating factors, and transcription initiation complexes involved in the transcriptional regulation of RORα will facilitate the development of synthetic ligands and their potential applications in diseases such as atherosclerosis, dyslipidemia, and diabetes. In this review, we discuss the current literature on the structure and function of RORα, the target genes regulated by RORα, and the potential of RORα as a therapeutic target for atherosclerosis.