Are those phospholipids in your pocket?

The identification of phospholipids ligands for the nuclear receptors SF-1 and LRH-1 raise exciting new questions in the areas of signaling and metabolism. Do these receptors provide cells with a mechanism to alter genomic activities in response to phospholipid flux? The tools now exist to address these questions, and more.

Identification of an agonist ligand for estrogen-related receptors ERRbeta/gamma.

In order to develop agonist ligands that are specific for the estrogen-related receptors ERRbeta/gamma, a hydrazone with a 4-hydroxy group at one phenyl ring and a 4-diethylamino moiety at the other phenyl ring was synthesized. We demonstrate that compound 3 (DY131; N'-{(1E)-[4-(diethylamino)phenyl]methylene}-4-hydroxybenzohydrazide) effectively and selectively activates ERRbeta/gamma. DY131 had no effect on the structurally related receptors ERRalpha or the estrogen receptors alpha and beta (ERalpha/beta). This work defines a convenient synthesis for a novel and selective pharmacologic tool that can be used to elucidate the biological activities of ERRbeta/gamma.

Detection of designer steroids.

Illicit use of performance-enhancing steroids has proliferated among a wide range of professional and amateur athletes. This problem has attracted broad public attention and has led the United States Congress to draft legislation that proposes frequent testing of athletes. However, current testing protocols are inadequate as athletes can evade detection by using novel steroids that are unknown to authorities. We have developed a strategy that overcomes this limitation by virtue of its ability to detect "designer steroids" without prior knowledge of their existence.

Linking lipids, Alzheimer's and LXRs?

Deposition of the beta-amyloid (Abeta) peptide is thought to underlie development of Alzheimer's disease (AD). This pathological linkage has spurred considerable interest in therapeutic strategies to reduce Abeta production. It is becoming increasingly clear that altered cholesterol homeostasis can modulate Abeta production and/or accumulation. In this review, we discuss the molecular pathology of AD, the cholesterol connection and recent data suggesting that the oxysterol receptor, liver X receptor LXR (NR1H2 and NR1H3), may modulate these events.

The nuclear receptor PXR: a master regulator of "homeland" defense.

Human beings are constantly exposed to toxic chemicals present in food and the environment. We are also challenged by toxic byproducts of chemical reactions within our own bodies. These toxins need to be inactivated or excreted to maintain homeostasis. Pregnane X receptor (PXR) is a promiscuous nuclear receptor that is activated by a diverse array of endogenous and exogenous toxins. On activation, PXR regulates a number of target genes involved in drug metabolism and efflux in two key target tissues: the liver and intestine. In this article, we review the data accumulated in the last few years identifying PXR as a central player in the integration of these pathways.

Constitutive activation of peroxisome proliferator-activated receptor-gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated nuclear receptor that has an essential role in adipogenesis and glucose homeostasis. PPAR-gamma is expressed in vascular tissues including endothelial cells (ECs). PPAR-gamma activity can be regulated by many pathophysiological and pharmacological agonists. However, the role of PPAR-gamma activation in ECs remains unclear. In this study, we examined the effect of the constitutive activation of PPAR-gamma on the phenotypic modulation of ECs. Adenovirus-mediated expression of a constitutively active mutant of PPAR-gamma resulted in significant ligand-independent activation of PPAR-gamma and specific induction of the PPAR-gamma target genes. However, PPAR-gamma activation significantly suppressed the expression of vascular adhesion molecules in ECs and the ensuing leukocyte recruitment. Furthermore, constitutive activation of PPAR-gamma resulted in simultaneous repression of AP-1 and NF-kappaB activity, which suggests that PPAR-gamma may reduce pro-inflammatory phenotypes via, at least in part, suppression of the AP-1 and NF-kappaB pathways. Therefore, using a gain-of-function approach, our study provides novel evidence showing that constitutive activation of PPAR-gamma is sufficient to prevent ECs from converting into a pro-inflammatory phenotype. These results also suggest that, in addition to pharmacological agonists, the genetic modification of the PPAR-gamma activity in ECs may be a potential approach for therapeutic intervention in various inflammatory disorders.

The antidiabetic agent LG100754 sensitizes cells to low concentrations of peroxisome proliferator-activated receptor gamma ligands.

Insulin resistance and non-insulin-dependent diabetes mellitus are major causes of morbidity and mortality in industrialized nations. Despite the alarming rise in the prevalence of this disorder, the initial molecular events that promote insulin resistance remain unclear. The data presented here demonstrate that LG100754, an antidiabetic RXR ligand, defines a novel type of nuclear receptor agonist. Surprisingly, LG100754 has minimal intrinsic transcriptional activity, instead it enhances the potency of proliferator-activated receptor (PPAR) gamma-retinoid X receptor heterodimers for PPARgamma ligands. The ability of LG100754 to both increase PPARgamma sensitivity and relieve insulin resistance implies that a deficiency in endogenous PPARgamma ligands may represent an early step in the development of insulin resistance.