Kevin Mouzat

Targeting liver X receptors in human health: deadlock or promising trail?

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 intracellular cholesterol ‘sensors’ whose activation leads to decreased plasma cholesterol. Their implication in other physiologic processes currently prevents their use as therapeutic targets, because of potentially deleterious side effects. Areas covered: The various LXR agonists and antagonists, along with the physiological functions of LXR. Putative clinical targets including atherosclerosis, diabetes, Alzheimers disease, skin disorders, reproductive disorders and cancer. Expert opinion: LXR are promising pharmacological targets because of the high potential to develop ligands owing to the variety of natural or synthetic agonists. Three aspects should be developed to select a LXR-ligand for treatment of human disease: bio-availability; isoform specificity; tissue specificity. This will allow the development of selective liver X modulators (SLiMs). The challenge is to overcome deleterious side effects to establish LXR as new pharmacological targets.

Oxysterol nuclear receptor LXRβ regulates cholesterol homeostasis and contractile function in mouse uterus

The uterus is an organ where lipid distribution plays a critical role for its function. Here we show that nuclear receptor for oxysterols LXRβ prevents accumulation of cholesteryl esters in mouse myometrium by controlling expression of genes involved in cholesterol efflux and storage (abca1 and abcg1). Upon treatment with an LXR agonist that mimics activation by oxysterols, expression of these target genes was increased in wild-type mice, whereas under basal conditions, lxrα;β-/- mice exhibited a marked decrease in abcg1 accumulation. This change resulted in a phenotype of cholesteryl ester accumulation. Besides, a defect of contractile activity induced by oxytocin or PGF2α was observed in mice lacking LXRβ. These results imply that LXRβ provides a safety valve to limit cholesteryl ester levels as a basal protective mechanism in the uterus against cholesterol accumulation and is necessary for a correct induction of contractions.

Endoglin (CD105) Expression Is Regulated by the Liver X Receptor Alpha (NR1H3) in Human Trophoblast Cell Line JAR

Human implantation involves invasion of the uterine wall and remodeling of uterine arteries by extravillous cytotrophoblasts. Defects in these early steps of placental development lead to poor placentation and are often associated with preeclampsia, a frequent complication of human pregnancy. One of the complex mechanisms controlling trophoblast invasion involves the activation of the liver X receptor beta (or NR1H2, more commonly known as LXRbeta) by oxysterols known as potent LXR activators. This activation of LXRbeta leads to a decrease of trophoblast invasion. The identification of new target genes of LXR in the placenta could aid in the understanding of their physiological roles in trophoblast invasion. In the present study, we show that the endoglin (ENG) gene is a direct target of the liver X receptor alpha (NR1H3, also known as LXRalpha). ENG, whose gene is highly expressed in syncytiotrophoblasts, is part of the transforming growth factor (TGF) receptor complex that binds several members of the TGFbeta superfamily. In the human placenta, ENG has been shown to be involved in the inhibition of trophoblast invasion. Treatment of human choriocarcinoma JAR cells with T0901317, a synthetic LXR-selective agonist, leads to a significant increase in ENG mRNA and protein levels. Using transfection and electrophoretic mobility shift assays, we demonstrate that LXR (as a heterodimer with the retinoid X receptor) is able to bind the ENG promoter on an LXR response element and mediates the activation of ENG gene expression by LXRalpha in JAR cells. This study suggests a novel mechanism by which LXR may regulate trophoblast invasion in pathological pregnancy such as preeclampsia.

A common polymorphism in NR1H2 (LXRbeta) is associated with preeclampsia

BackgroundPreeclampsia is a frequent complication of pregnancy and a leading cause of perinatal mortality. Both genetic and environmental risk factors have been identified. Lipid metabolism, particularly cholesterol metabolism, is associated with this disease. Liver X receptors alpha (NR1H3, also known as LXRalpha) and beta (NR1H2, also known as LXRbeta) play a key role in lipid metabolism. They belong to the nuclear receptor superfamily and are activated by cholesterol derivatives. They have been implicated in preeclampsia because they modulate trophoblast invasion and regulate the expression of the endoglin (CD105) gene, a marker of preeclampsia. The aim of this study was to investigate associations between the NR1H3 and NR1H2 genes and preeclampsia.MethodsWe assessed associations between single nucleotide polymorphisms of NR1H3 (rs2279238 and rs7120118) and NR1H2 (rs35463555 and rs2695121) and the disease in 155 individuals with preeclampsia and 305 controls. Genotypes were determined by high-resolution melting analysis. We then used a logistic regression model to analyze the different alleles and genotypes for those polymorphisms as a function of case/control status.ResultsWe found no association between NR1H3 SNPs and the disease, but the NR1H2 polymorphism rs2695121 was found to be strongly associated with preeclampsia (genotype C/C: adjusted odds ratio, 2.05; 95% CI, 1.04-4.05; p = 0.039 and genotype T/C: adjusted odds ratio, 1.85; 95% CI, 1.01-3.42; p = 0.049).ConclusionsThis study provides the first evidence of an association between the NR1H2 gene and preeclampsia, adding to our understanding of the links between cholesterol metabolism and this disease.

Mystery Case: CSF-1R mutation is a cause of intracranial cerebral calcifications, cysts, and leukoencephalopathy: [RETRACTED]

A 37-year-old man was referred for a 1-year history of word naming difficulties and progressive executive dysfunction along with anxiety. Clinical examination showed generalized hyperreflexia and bilateral Babinski sign but was otherwise normal. His brain MRI (figure, A and B) showed extensive leukoencephalopathy with multiple small cysts within the white matter changes and no gadolinium enhancement. CT identified punctate calcifications with deep frontal and juxtacortical distribution (figure, C and D). His mother died at 63 years after a 10-year history of progressive cognitive impairment of frontal type, walking difficulties, and urinary incontinence. Her brain imaging was strikingly similar to her sons (figure, E–H).

Slowly progressive motor neuron disease with multi-system involvement related to p.E121G SOD1 mutation

Abstract We report the third case of amyotrophic lateral sclerosis related to p.E121G Superoxide dismutase-1 (SOD1) mutation. Besides a sporadic presentation and a slow progressive course, as described in the 2 previously cases, our patient presented with prominent sensory and cerebellar signs. This case report strengthens that p.E121G should be considered as a causal mutation. Slowly upper and lower motor neuron degeneration, even with non-motor clinical features, should prompt a sequencing of SOD1.