Review
Nuclear receptors as drug targets in metabolic diseases: new approaches to therapy

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Nuclear receptors represent novel targets for the development of therapeutic agents for the treatment of numerous diseases, including type 2 diabetes, obesity dyslipidemia, atherosclerosis and the metabolic syndrome. There have been many recent advances in the development of new therapeutic agents for a subset of these receptors, including the peroxisome proliferator-activated receptors, the liver X receptors and the farnesoid X receptor. To date, the synthesis of selective modulators that regulate the activity of these receptors has been empirical. However, a detailed understanding of the molecular basis for selective modulation, as well as new insights into the biology of these receptors, might open the door to the rational design of a new generation of therapeutic agents with improved safety and efficacy.

Introduction

Nuclear receptors represent one of the largest families of transcription factors, with 48 present in the human genome. These receptors are activated through the binding of hydrophobic ligands, including fatty acids (FAs), hormones, bile acids and oxysterols. Nuclear receptors are modular in nature. They contain an amino-terminal ligand-independent activation function 1 transactivation domain, a DNA-binding domain containing two zinc finger motifs and a carboxy-terminal domain that contains a dimerization domain and a ligand-dependent activation function 2 transactivation domain [1]. Some nuclear receptors can bind DNA and activate transcription of their target genes as monomers but the majority of these receptors are active as homodimers or heterodimers bound to the retinoid X receptor. In the absence of a ligand, nuclear receptors form complexes with corepressors such as the nuclear receptor corepressor and the silencing mediator for retinoic acid receptor and thyroid hormone receptor 2, 3, 4, which repress transcription through the recruitment of histone deacetylases. Ligand binding induces a conformational change that results in the dissociation of corepressors and the recruitment of coactivators, such as peroxisome proliferator-activated receptor coactivator 1 and the cAMP response element-binding protein-binding protein–p300 5, 6, 7. The specificity of the complexes formed between the receptor and corepressors or coactivators appears to be determined by the cell type, the conformational change induced by the ligand and the sequence of the DNA-binding element. This level of complexity enables fine-tuning of the physiological response and explains the variability of gene expression changes when a receptor is activated by different ligands 8, 9.

The metabolism of glucose, fat, cholesterol and bile acids is controlled, in part, by a subset of nuclear receptors. In this review we focus on the function of the peroxisome proliferator-activated receptors (PPARs) [10], the liver X receptors (LXRs) and the farnesoid X receptor (FXR) [11] in human diseases, including type 2 diabetes, dyslipidemia, atherosclerosis and the metabolic syndrome (Table 1).

Section snippets

PPARs

There are three members of the PPAR family: PPAR-α, PPAR-γ, and PPAR-δ [10]. They are 60–80% conserved in their DNA- and ligand-binding domains and are activated by several natural and synthetic ligands, including eicosanoids, free fatty acids (FFAs), lipid-lowering drugs (the fibrates) and the insulin-sensitizing agents thiazolidinediones (TZDs).

LXRs

Two isoforms of LXR exist, and they function as intracellular sensors of oxysterol levels [11]. Expression is highest in the liver and intestine but LXR-α is also detected in macrophages, adipose tissue, kidney, lung and spleen, whereas LXR-β is ubiquitously expressed. The role of LXR in the enterohepatic system and in macrophages is best studied, and is discussed below [11].

LXRs are involved in cholesterol homeostasis. Mice deficient in LXR-α develop hepatomegaly and accumulate large

FXR

Similarly to the LXRs, FXR is highly expressed in the liver and intestine, and serves as a bile acid sensor [11]. Its natural ligands are bile acids, including cholic acid and chenodeoxycholic acid. Conversion of cholesterol to bile acids is the major pathway for elimination of cholesterol [66]. Bile acids are important for the digestion and absorption of lipids, fat-soluble vitamins and cholesterol from the intestinal tract. Ninety-five percent of secreted bile acids are reabsorbed by

Summary

Despite recent therapeutic advances, the prevalence of type 2 diabetes, insulin resistance and the metabolic syndrome has risen to epidemic proportions. Oral antidiabetic agents are moderately effective but their efficacy in controlling hyperglycemia is limited by dose-related tolerability, most notably weight gain. PPAR-γ partial agonists, PPAR-α and -γ dual agonists, PPAR-δ agonists and pan-agonists are currently being evaluated in clinical trials, and offer significant advantages relating to

Acknowledgements

We thank Dave Erbe, Vipin Suri and George Vlasuk for comments on the manuscript.

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