Modulation of Retinoic Acid Receptor-related Orphan Receptor α and γ Activity by 7-Oxygenated Sterol Ligands

Abstract

The retinoic acid receptor-related orphan receptors ␣ and ␥ (ROR␣ (NR1F1) and ROR␥ (NR1F3)) are orphan nuclear receptors and perform critical roles in regulation of development, metabolism, and immune function. Cholesterol and cholesterol sulfate have been suggested to be ROR␣ ligands, but the physiological significance is unclear. To date, no endogenous ROR␥ ligands have been described. Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both ROR␣ and ROR␥ by directly binding to their ligand-binding domains In the late 1980s, as the canonical domain structure and conserved sequence of members of the nuclear hormone receptor (NHR) 3 superfamily became apparent, several laboratories began to isolate additional members of this superfamily that had no identified ligands. Many of these so-called orphan receptors still have no identified ligands. The first member of the ROR subfamily of receptors (ROR␣) was identified in the early 1990s based on sequence similarities to the retinoic acid receptor and the retinoid X receptor, hence the name "retinoic acid receptor-related orphan receptor" (1, 2). The highly similar receptors, ROR␤ and ROR␥, were identified soon after (3, 4).

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

“…We provide evidence indicating that some of these genes are regulated directly by ROR␣. Recent studies have suggested that the activity of ROR␣ can be regulated by natural and synthetic compounds (30,55), which raises hopes that ROR␣ may provide a novel therapeutic target in the management and prevention of obesity and related pathologies, such as diabetes.…”

“…Recent studies have demonstrated that RORs function as ligand-dependent transcription factors (20,23,30,48,55). RORs have been implicated in the regulation of a wide variety of physiological processes, including cerebellar development, metabolism, circadian rhythm, cellular immunity, bone formation, hypoxia signaling, and inflammatory responses (4, 9, 11, 12, 16, 19, 20, 24, 29, 31-33, 42, 43, 47, 49, 54, 58, 60).…”

Upstream Stimulating Factors Regulate the Expression of RORγT in Human Lymphocytes

“…The basic RORC variant (RORg) is expressed ubiquitously and plays an important function in the regulation of development and metabolism (5). Recently, the 7-oxygenated sterol was identified as an endogenous ligand modulating the function of this transcription factor (6). The expression of RORgT (also termed RORC2) has a very restricted pattern, and its product is predominantly found in immune organs, such as thymus, and in particular lineages of immune cells, such as immature doublepositive thymocytes and Th17 lymphocytes (2,7), where this transcription factor plays important functions in the maturation of a/b T cells and the differentiation of Th17 cells, respectively (2,8).…”

Retinoic Acid-related Orphan Receptor α Regulates Diurnal Rhythm and Fasting Induction of Sterol 12α-Hydroxylase in Bile Acid Synthesis

“…The ligand binding pocket of ROR␣ contains cholesterol or cholesterol sulfate, which may be endogenous ROR␣ ligands (23,24). A recent study shows that 7␣-oxygenated cholesterols are high affinity ligands for ROR␣ and ROR␥ and that 7␣-hydroxycholesterol (7␣-OHC), a product of CYP7A1, is an inverse agonist of ROR␣ that decreases ROR␣ transcriptional activation of gluconeogenic genes to reduce hepatic glucose output (25). This could be a mechanism linking bile acid synthesis to inhibit gluconeogenesis.…”