Going nuclear in metabolic and cardiovascular disease

Abstract

Estrogen receptors, PPARs, and liver X receptors are members of the nuclear receptor superfamily of ligand-dependent transcription factors that regulate diverse aspects of development and homeostasis. Recent studies of the biologic roles of these receptors and their mechanisms of action have significantly advanced our understanding of transcriptional programs that control lipid and carbohydrate metabolism, immunity and inflammation, and wound repair. These findings provide insights into the therapeutic actions of existing drugs that target nuclear receptors and raise new possibilities for development of safer, more effective drugs for the prevention and treatment of metabolic and cardiovascular diseases. In this introduction to this Review series, underlying mechanisms that enable nuclear receptors to positively and negatively regulate gene expression are presented as background to the focused reviews on estrogen receptors, PPARs, liver X receptors, and the PPARgamma coactivator-1 (PGC-1) family of coactivators.

Figure 1

Domain structure of nuclear receptors. N and C represent the amino and carboxyl termini, respectively. AF1 is a variable amino-terminal transactivation domain. The ligand-binding domain (LBD) also mediates dimerization, transcriptional activation, and transcriptional repression functions. DBD, DNA-binding domain.

Figure 2

Mechanisms of sequence-specific DNA binding by steroid hormone and heterodimeric nuclear receptors. (A) Steroid hormone receptors, such as the ER and glucocorticoid receptor (GR), generally bind as homodimers in a ligand-dependent manner to hormone REs that consist of palindromic arrangements of core recognition motifs (arrows). (B) RXR heterodimers bind in the presence or absence of ligands (shown here in the presence of ligand) to similar core recognition elements arranged as direct repeats. Both the specific sequence of the core recognition motif and the spacing between motifs are determinants of DNA-binding specificity. PPAR/RXR heterodimers preferentially bind to direct repeats spaced by 1 bp, while LXR/RXR heterodimers preferentially bind to direct repeats spaced by 4 bp.

Figure 3

Mechanisms of transcriptional activation and repression by steroid hormone and heterodimeric nuclear receptors. (A) Ligand-dependent transactivation. The binding of hormones or synthetic agonists causes the recruitment of coactivator complexes to the ligand-binding domain. Ligand-dependent recruitment of these factors is similar for heterodimeric receptors and steroid hormone receptors (not shown). For simplicity, only a single generic complex is illustrated. In general, ligand-dependent transcription of nuclear receptor target genes is associated with the recruitment of numerous coactivator complexes that act in a combinatorial or sequential manner. These complexes are associated with a number of enzymatic activities, including histone acetyltransferase (HAT), histone methyltransferase (HMT), and nucleosome remodeling (NRM) activities. Structurally distinct ligands may alter the pattern of recruitment of these factors, resulting in altered patterns of gene activation. (B) Active repression. A subset of heterodimeric nuclear receptors, including PPAR/RXR and LXR/RXR heterodimers, are capable of binding to REs in the absence of ligand and recruiting corepressor complexes that actively repress transcription. A number of corepressor complexes are associated with histone deacetylase (HDAC) activities, as well as histone methyltransferase and nucleosome remodeling activities that are generally distinct from those associated with coactivator complexes. HDM, histone demethylase. (C) SERM/antagonist–dependent repression. Some SERMs (shown here in gray), such as tamoxifen, and PPAR antagonists promote corepressor interactions with the ligand-binding domain, resulting in active repression in permissive cell types. (D) Ligand-dependent trans-repression. Many nuclear receptors, including glucocorticoid receptors, ERs, PPARs, and LXRs (indicated in blue), are capable of antagonizing signal-dependent activation of inflammatory response genes by transcription factors such as NF-κB.