The cDNA for a member of the nuclear receptor family was cloned and named ubiquitous receptor (UR), since UR protein and mRNA are detected in many cell types. Rat UR/human retinoid X receptor a (hRXRa) heterodimers bound preferentially to double-stranded oligonucleotide direct repeats having the consensus half-site sequence AGGTCA and 4-nt spacing (DR-4). Coexpression of UR in COS-1 cells inhibited the stimulation of chloramphenicol acetyltransferase (CAT) reporter gene expression by hRXRa and human retinoic acid, receptor a in the presence of all-transretinoic acid when DR-4 (but not DR-5) was present upstream of the promoter of a CAT reporter gene (DR-4-CAT). UR expression also inhibited the activation of a DR-4-CAT reporter gene by hRXRa and 9-cis-retinoic acid or by thyroid hormone receptor a in the, presence of thyroid hormone. However, in the absence of 9-cis-retinoic acid, UR in combination with hRXRa stimulted DR-4-CAT expression. Coex (4,5). The nature of the DNA flanking these half-sites also is important in determining the specificity of a response element (6). Homodimers of the thyroid hormone/retinoid receptor family are also able to modulate transcriptional activity in different ways than their heterodimeric forms (7). The effect of these homo-and heterodimeric receptors on transcriptional activity also depends on their occupancy by specific ligands (8). The complexity of this network of interacting factors is increasing with the discovery of new members of this superfamily of nuclear receptors, many of which are called orphan receptors, since they lack known ligands. An interplay of receptors, ligands, response elements, and yet-to-be-discovered factors may ultimately control the activity of these transcriptional factors and ensure the appropriate cellular responses during development and in the adult.We report here our discovery of a member of the nuclear receptor family of transcription factors that we have named ubiquitous receptor (UR),t because of its wide tissue distribution. UR is not an isoform of any known receptor and interacts with the response elements and network of receptors in the thyroid receptor (TR)/retinoic acid receptor (RAR) subfamily.

Excessive cholesterol is eliminated from extrahepatic cells by reverse cholesterol transport, a process by which neutral sterols are transferred to extracellular acceptor lipoproteins for further transport to the liver. Another process independent of lipoproteins involves excretion of 3beta-hydroxy-5-cholesten-25(R)-26-carboxylic (cholestenoic) acid, a metabolite of 27-hydroxycholesterol. Physiological concentrations of cholestenoic acid activated the nuclear receptor liver X receptor alpha (LXR alpha; NR1H3), but not other oxysterol receptors. As a ligand, cholestenoic acid modulated interaction of LXR alpha with the nuclear receptor coactivator Grip-1. Cholestenoic acid, therefore, may function as a signaling molecule for regulation of lipid metabolism via LXR alpha.

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