Liver X receptor is a regulator of orphan nuclear receptor NOR-1 gene transcription in adipocytes

Abstract

Objective: 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. Approach: White and brown adipose tissues from wild-type, LXRaÀ/À-and LXRa:b-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 wildtype or LXRaÀ/À mice differentiated into adipocytes. Results: In LXRaÀ/À-and LXRa:b-deficient adipocytes, basal levels of NOR-1 were significantly reduced while retaining an equivalent proportional induction by b-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 À997 bp of the NOR-1 promoter, which was shown to be functional by promoter reporter gene activity, gel shift and chromatin immunoprecipitation assays. Conclusion: 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.

Dendrogenin A drives LXR to trigger lethal autophagy in cancers

“…3f ). We therefore investigated the hypothesis that DDA could modulate the liver-X-receptors (LXRs) as DDA-induced events such as triacylglycerol synthesis 5 , 9 and NOR1 expression are also known to be regulated by the LXRs 27 . We found that DDA inhibited LXR-dependent luciferase activity stimulated by 22(R)-hydroxycholesterol (22(R)HC) in the presence of LXRα or LXRβ in a concentration-dependent manner, with IC 50 values of 362 ± 52 and 76 ± 12 nM, respectively (Fig.…”

The roles of liver X receptor α in inflammation and inflammation‐associated diseases

“…Overexpression of NOR‐1 in macrophages reduces the synthesis of inflammatory cytokines and chemokines (van Tiel & de Vries, 2012). A previous study discovered that LXRs and NOR‐1 have an interdependent regulatory association and LXRs are a regulator of NOR‐1 gene transcription in adipocytes (Kumar et al, 2009). Subsequent research also uncovered that LXRα activation elevates NOR‐1 expression in Kupffer cells, which in turn upregulates cytokines (including TNF‐α and IL‐10) to resist LPS‐induced inflammation (K. He et al, 2015).…”

A long-non-coding RNA, LINC00473, confers the human adipose tissue thermogenic phenotype through enhanced cAMP responsiveness

“…LINC00473 has been reported to interact with NONO, a protein that interacts with cyclic AMP-responsive-element-binding protein (CREB) -regulated transcription coactivator (CRCT), which is essential in CREB transcriptional regulation (Chen et al, 2016). CREB directly and through interaction with NR4A3, (Cannon and Nedergaard, 2004;Kozak et al, 1994;Yubero et al, 1998;Yubero et al, 1994 ), activates the UCP1 promoter (Kumar et al, 2008;Myers et al, 2009;Pearen and Muscat, 2010). It is possible that LINC00473 may coordinate the actions of transcription factors that regulate the UCP1 promoter.…”