NR1D - nuclear receptor subfamily 1 group D member | Elisa - Clia - Antibody - Protein

Background

Nuclear receptor subfamily 1 group D member (NR1D) comprises two closely related genes, NR1D1 and NR1D2, which encode the nuclear receptors REV-ERBα and REV-ERBβ, respectively. These receptors are integral components of the circadian rhythm regulation and metabolic processes. NR1D1 (REV-ERBα) was first identified as an orphan nuclear receptor with no known endogenous ligands but later found to be a critical player in the maintenance of circadian rhythms and metabolic homeostasis. NR1D2 (REV-ERBβ) shares similar functions but differs in tissue distribution and regulatory roles. Both receptors function as transcriptional repressors, modulating the expression of genes involved in circadian rhythm, metabolism, and inflammation.

Protein Structure

The NR1D proteins share a common structure typical of nuclear receptors:

• DNA-Binding Domain (DBD): This highly conserved domain contains two zinc finger motifs that allow the receptor to bind to specific DNA sequences known as Rev-Erb response elements (RevREs).
• Ligand-Binding Domain (LBD): Although originally classified as orphan receptors, NR1D1 and NR1D2 have been found to bind heme, a porphyrin derivative, which acts as a ligand regulating their activity.
• Transcriptional Repression Domain: These proteins possess domains that recruit co-repressor complexes, such as NCoR (nuclear receptor co-repressor) and HDAC3 (histone deacetylase 3), to inhibit gene transcription.

Classification and Subtypes

NR1D receptors belong to the nuclear receptor superfamily, specifically classified under subfamily 1, group D. The two main subtypes are:

• NR1D1 (REV-ERBα): Highly expressed in the liver, skeletal muscle, and adipose tissue.
• NR1D2 (REV-ERBβ): Expressed in the brain, adipose tissue, and skeletal muscle, with a broader distribution than NR1D1.

Function and Biological Significance

The NR1D receptors play crucial roles in various physiological processes:

• Circadian Rhythm Regulation: NR1D1 and NR1D2 are integral components of the circadian clock, repressing the expression of BMAL1 and CLOCK genes, which are essential for maintaining the circadian rhythm.
• Metabolism: These receptors regulate lipid and glucose metabolism by controlling the expression of genes involved in these pathways. They help synchronize metabolic processes with the circadian cycle.
• Inflammation: NR1D1 and NR1D2 modulate inflammatory responses by repressing the expression of pro-inflammatory cytokines and genes involved in immune responses.
• Development and Differentiation: NR1D proteins are involved in the differentiation of adipocytes and the development of skeletal muscle.

Clinical Issues

• Metabolic Disorders: Dysregulation of NR1D1 and NR1D2 is linked to metabolic disorders such as obesity, diabetes, and dyslipidemia. Their roles in regulating lipid and glucose metabolism make them potential therapeutic targets for these conditions.
• Circadian Rhythm Disorders: Disruption in the expression or function of NR1D receptors can lead to circadian rhythm disorders, affecting sleep patterns and overall health.
• Inflammatory Diseases: Given their role in modulating inflammation, NR1D receptors are implicated in chronic inflammatory diseases and conditions such as atherosclerosis.

Summary

NR1D1 and NR1D2 (REV-ERBα and REV-ERBβ) are critical nuclear receptors involved in maintaining circadian rhythms, metabolic homeostasis, and regulating inflammation. Their ability to act as transcriptional repressors by binding to specific DNA elements and recruiting co-repressor complexes underscores their importance in gene regulation. Dysregulation of these receptors is associated with various metabolic and inflammatory diseases, highlighting their potential as therapeutic targets for treating these conditions.