Nuclear receptors

Peroxisome proliferator-activated receptors (PPARs) are pharmacological targets for the treatment of metabolic disorders. Previously, we demonstrated the anti-diabetic effects of SR1664, a PPARγ modulator lacking classical transcriptional agonism, despite its poor pharmacokinetic properties. Here, we report identification of the antagonist SR11023 as a potent insulin sensitizer with significant plasma exposure following oral administration. To determine the structural mechanism of ligand-dependent antagonism of PPARγ, we employed an integrated approach combining solution-phase biophysical techniques to monitor activation helix (helix 12) conformational dynamics. While informative on receptor dynamics, hydrogen/deuterium exchange mass spectrometry and nuclear magnetic resonance data provide limited information regarding the specific orientations of structural elements. In contrast, label-free quantitative crosslinking mass spectrometry revealed that binding of SR11023 to PPARγ enhanc...

Age-related hearing loss is the most common type of hearing impairment, and is typically characterized by the loss of spiral ganglion neurons (SGNs). The two Liver X receptors (LXRs) are oxysterol-activated nuclear receptors which in adults, regulate genes involved in cholesterol homeostasis and modulation of macrophage activity. LXR β plays a key role in maintenance of health of dopaminergic neurons in the substantia nigra, large motor neurons in the spinal cord, and retinal ganglion cells in adult mice. We now report that LXR β is expressed in the SGNs of the cochlea and that loss of LXR β leads to age-related cochlea degeneration. We found that in the cochlea of LXR β-/- mice, there is loss of SGNs, activation of macrophages, demyelination in the spiral ganglion, decrease in glutamine synthetase (GS) expression and increase in glutamate accumulation in the cochlea. Part of the cause of damage to the SGNs might be glutamate toxicity which is known to be very toxic to these cells. Our study provides a so far unreported role of LXR β in maintenance of SGNs whose loss is a very common cause of hearing impairment.

Non-alcoholic fatty liver disease (NAFLD) is an emerging epidemic in light of its two predisposing factors, a surge in both obesity and diabetes rates with reports of between 70-80% of obese individuals in Western countries. The disease progression of NAFLD remains elusive but is generally attributed to insulin resistance, lipid metabolism dysfunction, altered immune response to name a few. Potential therapeutic strategies should target one or some of these pathological events in the liver, however currently no specific therapies for NAFLD exist. Thus novel therapeutic approaches to manage the chronic liver disease epidemic are becoming essential. In this review we discuss the evidence supporting the role of bile acid activated Farnesoid X Receptor (FXR) in promoting lipid oxidation, reducing inflammation and fibrosis in the liver. We also examine the potential of FXR agonists, as an attractive class of drugs for the safe and effective treatment of NAFLD.

Targeting peroxisome proliferator-activated receptor γ (PPARγ) by synthetic compounds has been shown to elicit insulin sensitising properties in type 2 diabetics. Treatment with a class of these compounds, the thiazolidinediones (TZDs), has shown adverse side effects such as weight gain, fluid retention, and congestive heart failure. This is due to their full agonist properties on the receptor, where a number of genes are upregulated beyond normal physiological levels. Lessened transactivation of PPARγ by partial agonists has proved beneficial in terms of reducing side effects, while still maintaining insulin sensitising properties. However, some partial agonists have been associated with unfavourable pharmacokinetic profiles due to their acidic moieties, often causing partitioning to the liver. Here we present SR1988, a new partial agonist with favourable non-acid chemical properties. We used a combination of X-ray crystallography and hydrogen/deuterium exchange (HDX) to elucidate the structural basis for reduced activation of PPARγ by SR1988. This structural analysis reveals a mechanism that decreases stabilisation of the AF2 coactivator binding surface by the ligand.

Molecular chaperones encompass a group of unrelated proteins that facilitate the correct assembly and disassembly of other macromolecular structures, which they themselves do not remain a part of. They associate with a large and diverse set of coregulators termed cochaperones that regulate their function and specificity. Amongst others, chaperones and cochaperones regulate the activity of several signaling molecules including steroid receptors, which upon ligand binding interact with discrete nucleotide sequences within the nucleus to control the expression of diverse physiological and developmental genes. Molecular chaperones and cochaperones are typically known to provide the correct conformation for ligand binding by the steroid receptors. While this contribution is widely accepted, recent studies have reported that they further modulate steroid receptor action outside ligand binding. They are thought to contribute to receptor turnover, transport of the receptor to different subc...

Molecular mechanisms that influence susceptibility to multiple sclerosis are poorly understood. We analyzed peripheral blood gene expression profiles in nine healthy subjects up to nine years before the onset of multiple sclerosis in comparison with 11 age-, gender-, and origin-matched healthy subjects who remained multiple sclerosis-free, and 31 subjects during the first clinical episode of multiple sclerosis. Within the 1051 highly variable genes that differentiated between multiple sclerosis-to-be and multiple sclerosis-free subjects, we identified activation of TCR signaling that triggered the Cbl and MAPK cascade in concert with downstream synergic over-expression of NFAT and MEF2B, but failed to augment the expression of the nuclear receptor gene family members NR4A1, NR2F1, VDR and MEF2B, that further resulted in impaired apoptotic machinery. Comparison between multiple sclerosis-to-be and first clinical onset of multiple sclerosis operating module networks demonstrated the evolution of altered regulation of nuclear receptor-dependent apoptosis. Our findings demonstrating a silent multiple sclerosis trait that is associated with suppressed expression of the nuclear receptor network and inhibited apoptosis of activated T-cells support the role of these transcription signals in the evolution of the autoimmune processes that operate in the pre-disease stage of multiple sclerosis.

Nuclear receptors (NR) constitute a large family of proteins and play a crucial role in regulating mineral metabolism and physiological homeostasis of various organ systems. The aim of this study was to elucidate whether the variance among NRs of estrogen, androgen and vitamin-D in various vertebrate species including humans is attributed to differences between the taxonomic groups within a specific receptor (i.e. between orthologous) or between the different proteins within the taxon (i.e. between paralogous genes). Published data on 57 protein sequences of the above NRs were used for phylogenetic analysis. The results showed that in DNA- and ligand-binding regions, 94% and 70% of variance is due to differences between the three proteins. However, in non-binding regions, 47% of the variance results from differences between the three paralogous proteins. Human sequences consistently clustered with their mammal orthologous within the three groups of NR sequences, clearly indicating t...

Abstract: Introduction: Liver X receptors (LXR) are transcription factors that belong to the nuclear receptor superfamily. Natural derivatives of cholesterol, known as oxysterols, have been identified as agonistic ligands of LXR. They are thus mainly considered to be ...