NR4A orphan nuclear receptors: transcriptional regulators of gene expression in metabolism and vascular biology

Abstract

Members of the nuclear hormone receptor superfamily, including the peroxisome proliferator-activated receptor and the liver X receptor subfamilies, orchestrate transcriptional networks involved in the control of metabolism and the development of vascular disease. In addition to these well-characterized ligand-activated transcription factors, the nuclear receptor (NR) superfamily comprises many orphan receptors, whose ligands and physiological functions remain unknown. Among this group of orphan receptors is the NR4A subfamily, including Nur77 (NR4A1), Nurr1 (NR4A2), and NOR1 (NR4A3). These orphan NRs constitute an evolutionary ancient and highly conserved group of transcription factors. In contrast to other members of the superfamily, NR4A receptors function as ligand-independent transcription factors and immediate- or early-response genes, which are rapidly induced by a pleiotropy of environmental cues. Early functional studies have pointed to a critical role of NR4A receptors in regulating differentiation, proliferation, and apoptosis. More recent research has characterized NR4A receptors as key transcriptional regulators of glucose and lipid homeostasis, adipogenesis, inflammation, and vascular remodeling. In this review, we will summarize recent advances in understanding the molecular biology and physiological functions of NR4A receptors and discuss their role in the transcriptional control of metabolism and vascular remodeling.

Figure 1

NR4A Receptor Function in Metabolism and Energy Balance. NR4A orphan nuclear receptors are potently induced by physiological and pathological stimuli in liver, muscle and adipose tissue. In these tissues, NR4A orphan receptors function as transcriptional regulators of gene expression programs involved in the control of glucose homeostasis, lipid metabolism, and energy expenditure (see text for details).

Figure 2

Expression and Function of NR4A Receptors in Vascular Cells. NR4A orphan nuclear receptors are induced in vascular cells by a variety of stimuli, including inflammatory mediators, cytokines, hypoxia, and growth factors. In response to these pathophysiological environmental cues, NR4A receptors modulate gene expression leading to cell-specific processes (see text for details).