Liver X receptor is a regulator of orphan nuclear receptor NOR-1 gene transcription in adipocytes.
The liver X receptors (LXRs) are ligand-activated nuclear transcription factors that have been shown to play major roles in lipid, glucose and cholesterol metabolism. Recently, members of the NR4A orphan nuclear receptor family have also been shown to regulate the expression of important genes in metabolically active tissues such as liver, adipose and skeletal muscle. Here, we investigated the role of LXRs to regulate the expression of the nuclear receptor NOR-1 (neuron-derived orphan receptor-1) in adipocytes. White and brown adipose tissues from wild-type, LXRalpha-/-- and LXRalpha:beta-deficient mice were collected from animals at room temperature or following cold exposure to measure NOR-1 mRNA. The expression of NOR-1 and its promoter activity in response to LXR ligands were determined in cultured primary brown adipocytes or mouse embryo fibroblasts derived from wild-type or LXRalpha-/- mice differentiated into adipocytes. In LXRalpha-/-- and LXRalpha:beta-deficient adipocytes, basal levels of NOR-1 were significantly reduced while retaining an equivalent proportional induction by beta-adrenergic agonists. This reduced basal expression of NOR-1 in adipose tissue from LXR-deficient mice is a cell-autonomous event as it was also preserved in adipocytes differentiated from mouse embryo fibroblasts derived from these mice. In cultured primary brown adipocytes or cell lines, the expression of NOR-1 increased in response to an LXR agonist. A DNA sequence element (DR-4) capable of binding LXRs was found at -997 bp of the NOR-1 promoter, which was shown to be functional by promoter reporter gene activity, gel shift and chromatin immunoprecipitation assays. These data describe a new role for LXR to regulate NOR-1 gene expression in adipocytes and demonstrate that these two nuclear receptors have an interdependent regulatory relationship, in addition to each being involved in the control of metabolic fuel usage.