The “CholesteROR” Protective Pathway in the Vascular System

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Abstract
Retinoic acid receptor-related Orphan Receptor α (RORα) is a member of the nuclear hormone receptor superfamily. RORα has long been considered as a constitutive activator of transcription in the absence of exogenous ligand; however, cholesterol has recently been identified as a natural ligand of RORα. The spontaneous staggerer (sg/sg) mutation is a deletion in the Rora gene that prevents the translation of the ligand-binding domain (LBD), leading to the loss of RORα activity. The homozygous Rora sg/sg mutant mouse, of which the most obvious phenotype is ataxia associated with cerebellar degeneration, also displays a variety of other phenotypes, including several vascular ones; in particular, dysfunction of smooth muscle cells and enhanced susceptibility to atherosclerosis. Moreover, RORα appears to participate in the regulation of plasma cholesterol levels, and has been shown to positively regulate apolipoprotein (apo)A-I and apoC-III gene expression. Yet its activity is regulated by cholesterol itself, making RORα an intracellular cholesterol target.