Cholesterol Sensor Research Articles

SREBP1 promotes the invasion of colorectal cancer accompanied upregulation of MMP7 expression and NF-\u03baB pathway activation

BackgroundSterol-regulatory element binding protein 1 (SREBP1), an intracellular cholesterol sensor located in the endoplasmic reticulum, regulates the intracellular cholesterol by the Insig-Srebp-Scap pathway. Over-expression of SREBP1 can cause dyslipidemia. SREBP1 can regulate the metabolic pathway, and then promote the proliferation of tumor cells. However, there is no relevant research of metastasis and invasion in the field of colorectal cancer (CRC).MethodsExpression of SREBP1 was manipulated in CRC cell lines with low and high level SREBP1 expression by transfectiong with plasmids containing the SREBP1 gene, or by shRNA. The effect of SREBP1 on cell migration was assayed. The expression of SREBP1, p65 and MMP7 were detected by western blot. Human umbilical vein endothelial cell was used for detection of angiogenesis by adding the culture supernatant from HT29 and SW620. The level of reactive oxygen species (ROS) was detected by Dihydroethidium (DHE) staining. NF-κB inhibitor SN50 was used to test the relationship of SREBP1, NF-κB pathway and MMP7.ResultsWe found that the expression of SREBP1 in colon adenocarcinoma was significantly higher than that in noncancerous tissues, especially in the invasive tumor front including tumor budding. In vitro, SREBP1 over-expressed in colon cancer cell lines HT29 promoted angiogenesis in endothelial cells, increased ROS levels, phosphorylation of NF-κB-p65 and increases MMP7 expression. The effect of SREBP1 on expression of MMP7 was lost following treatment with the NF-κB inhibitor SN50.ConclusionOur results suggest that SREBP1 can promote the invasion and metastasis of CRC cells by means of promoting the expression of MMP7 related to phosphorylation of p65.

SREBP Plays a Regulatory Role in LH/hCG Receptor mRNA Expression in Human Granulosa-Lutein Cells

LH receptor (LHR) expression has been shown to be regulated posttranscriptionally by LHR mRNA binding protein (LRBP) in rodent and human ovaries. LRBP was characterized as mevalonate kinase. The gene that encodes mevalonate kinase is a member of a family of genes that encode enzymes involved in lipid synthesis and are regulated by the transcription factor sterol regulatory element binding proteins (SREBPs). The current study examined the regulation of LHR mRNA expression in human granulosa-lutein cells in response to alterations in cholesterol metabolism. Using atorvastatin, an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase to inhibit cholesterol biosynthesis, we examined its effect on LHR mRNA expression. The effect of atorvastatin on SREBP and mRNA expression as well as LHR mRNA binding protein expression was examined. Finally, the effect of atorvastatin on human chorionic gonadotropin (hCG)-stimulated progesterone production and the expression of key steroidogenic enzymes was also examined. Statin treatment reduced LHR mRNA expression by increasing the levels of SREBP1a and SREBP2, leading to an increase in LRBP. RNA gel shift assay showed that increased binding of LHR mRNA to LRBP occurred in response to atorvastatin, leading to LHR mRNA degradation. The granulosa-lutein cells pretreated with atorvastatin also showed decreased responsiveness to hCG by decreasing the mRNA and protein expression of steroidogenic enzymes. Atorvastatin also attenuated LH/hCG-induced progesterone production. These results imply that LHR mRNA expression by the human granulosa-lutein cells is regulated by cholesterol, through a mechanism involving SREBP and SREBP cleavage activating protein serving as the cholesterol sensor.

Oat fiber inhibits atherosclerotic progression through improving lipid metabolism in ApoE−/− mice

Cardiovascular diseases caused by atherosclerosis have become one of the leading cause of death. The aim of the present study was to explore how oat fiber regulated lipid metabolism and to elucidate its anti-atherosclerotic potential in ApoE−/− mice. Animals were daily fed a high-fat diet without or with 0.8% oat fiber for 18 weeks. Both serum total cholesterol and low-density cholesterol levels decreased in mice received oat fiber administration than those without Oat fiber inhibited hepatic lipid accumulation by downregulating SREBP-1 expression and accelerated clearance of intestinal cholesterol by upregulating SREBP-2 expression. In addition, oat fiber activated cholesterol sensors LXRα, and then strengthened hepatic and intestinal cholesterol efflux by increasing ATP-binding cassette A1 and G1, and decreased intestinal cholesterol absorption by inhibiting Niemann pick C 1 like 1. The findings implicated that oat fiber had an anti-atherosclerotic potential via mechanisms of activating the SREBPs/LXRα pathway and improving lipid metabolism.

CYP27A1 inhibits bladder cancer cells proliferation by regulating cholesterol homeostasis

ABSTRACTCYP27A1, an enzyme involved in regulating cellular cholesterol homeostasis, converts cholesterol into 27-hydroxycholesterol (27-HC). The relationship between CYP27A1 and cell proliferation was studied to determine the role of CYP27A1 in bladder cancer. The expression of CYP27A1 in three bladder cancer cell lines (T24, UM-UC-3 and 5637) were assessed by qRT-PCR and Western blotting, and cells with stable CYP27A1 expression were generated by lentiviral infection. Cell proliferation was detected by MTT assays, colony formation assays and a tumor xenograft model in vitro and in vivo, and the intracellular 27-HC and cholesterol secretion levels were detected by enzyme-linked immunosorbent assays (ELISA). The results revealed that CYP27A1 expression was downregulated in androgen receptor (AR)-positive T24/UM-UC-3 cells compared with AR-negative 5637 cell. After CYP27A1 expression was restored, cell proliferation was inhibited in vitro and in vivo because much more intracellular 27-HC was produced in the CYP27A1-overexpressing cells than in the control cells. Both T24 and UM-UC-3 cells treated with 27-HC showed similar results. In addition, CYP27A1/27HC could reduce the cellular cholesterol level in both T24 and UM-UC-3 cells by upregulating ATP-binding cassette transporters G1 and A1 (ABCG1 and ABCA1) through Liver X receptors (LXRs) pathway and downregulating low-density lipoprotein receptor (LDLR) expression. These findings all suggest that CYP27A1 is a critical cholesterol sensor in bladder cancer cells that may contribute significantly to bladder cancer proliferation.

SCAP knockdown in vascular smooth muscle cells alleviates atherosclerosis plaque formation via up-regulating autophagy in ApoE-/- mice.

Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a cholesterol sensor that plays a critical role in regulating intracellular cholesterol levels, but the association between SCAP and foam cell formation in vascular smooth muscle cells (VSMCs) is poorly understood. Using tissue-specific SCAP knockdown in apolipoprotein E (ApoE)-/- mice, we sought to search the mechanism through which SCAP signaling affects VSMC foam cell development. VSMC-specific SCAP knockdown mice were generated by Cre/LoxP-mediated gene targeting in ApoE-/- mice. Breeding SCAPflox/flox mice with SM22α-Cre mice resulted in no viable offspring with the homozygote SM22-Cre: SCAPflox/flox genotype due to embryonic lethality. We found that the heterozygote SM22α-Cre:SCAPflox/+:ApoE-/- mice fed a Western diet for 12 wk had significantly fewer atherosclerotic plaques in their aortas than the control mice due to reduced cholesterol uptake and synthesis. Furthermore, we found that autophagy in VSMCs was increased in SM22α-Cre:SCAPflox/+:ApoE-/- mice. Similarly, in vitro, SCAP knockdown in human coronary artery VSMCs by RNA interference reduced lipid accumulation and increased autophagy under LDL cholesterol loading. SCAP knockdown in VSMCs reduced oxidative stress and increased AMPK phosphorylation, which contributed to the up-regulation of autophagy in vivo and in vitro. VSMC-specific SCAP knockdown decreased the lipid accumulation and intracellular oxidative stress, increased excessive lipid clearance by enhancing lipid autophagy mediated by the reactive oxygen species/AMPK pathway in VSMCs, and consequently alleviated atherosclerosis plaque formation.-Li, D., Chen, A., Lan, T., Zou, Y., Zhao, L., Yang, P., Qu, H., Wei, L., Varghese, Z., Moorhead, J. F., Chen, Y., Ruan, X. Z. SCAP knockdown in vascular smooth muscle cells alleviates atherosclerosis plaque formation via up-regulating autophagy in ApoE-/- mice.

New Insights in Prostate Cancer Development and Tumor Therapy: Modulation of Nuclear Receptors and the Specific Role of Liver X Receptors.

Prostate cancer (PCa) incidence has been dramatically increasing these last years in westernized countries. Though localized PCa is usually treated by radical prostatectomy, androgen deprivation therapy is preferred in locally advanced disease in combination with chemotherapy. Unfortunately, PCa goes into a castration-resistant state in the vast majority of the cases, leading to questions about the molecular mechanisms involving the steroids and their respective nuclear receptors in this relapse. Interestingly, liver X receptors (LXRα/NR1H3 and LXRβ/NR1H2) have emerged as new actors in prostate physiology, beyond their historical roles of cholesterol sensors. More importantly LXRs have been proposed to be good pharmacological targets in PCa. This rational has been based on numerous experiments performed in PCa cell lines and genetic animal models pointing out that using selective liver X receptor modulators (SLiMs) could actually be a good complementary therapy in patients with a castration resistant PCa. Hence, this review is focused on the interaction among the androgen receptors (AR/NR3C4), estrogen receptors (ERα/NR3A1 and ERβ/NR3A2), and LXRs in prostate homeostasis and their putative pharmacological modulations in parallel to the patients’ support.

Highly Sensitive Nonenzymatic Cholesterol Sensor Based on Zinc Oxide Nanorods

This study investigated a highly sensitive nonenzymatic biosensor based on ZnO nanorods (NRs) for cholesterol concentration monitoring. The electrochemical behavior of the biosensor was studied by cyclic voltammetry, electrochemical impedance spectroscopy, and amperometric response in a 20 mM phosphate-buffered saline solution containing cholesterol. Results showed that this behavior was influenced by cholesterol oxidation, which occurs at the allylic position and is controlled by the electron transfer rate. The experimental parameters (pH, cholesterol concentration, and scan rate) influencing the output signal of the sensor were optimized. Under optimum conditions, the nonenzymatic cholesterol biosensor showed a linear response range of 1–9 mM, and the biosensor sensitivity was 4.2 μA mM−1 cm−2 for the ZnO-NRs-based biosensor and 135.5 μA mM−1 cm−2 for the Ag-nanoparticles (NPs)/ZnO-NRs-based biosensor. The detection limit was 1.78 mM and 0.184 mM, respectively. The reproducibility, stability, and reusability of the nonenzymatic cholesterol sensor were also investigated.

Cholesterol Homeostasis and Liver X Receptor (LXR) in Atherosclerosis

Cholesterol is an important lipid for maintaining cell membrane fluidity and generation of various hormones and bile acids. Thus, it is critical to maintain cholesterol homeostasis including absorption, trafficking, biosynthesis, and efflux; dysregulation of cholesterol homeostasis may lead to human disorders such as atherosclerosis. As a cholesterol sensor, nuclear receptor liver X receptor (LXR) is an important factor regulating cholesterol homeostasis. Extensive research has been carried out to examine the roles of LXR in atherosclerosis. In this review, we summarize our current understanding of the mechanisms how LXR regulates cholesterol synthesis, efflux, absorption, and conversion of cholesterol esters to cholesterol in the context of atherosclerosis. In addition, we also discuss the possibility of targeting LXR and cholesterol homeostasis as a potential interventional strategy for treating atherosclerosis.

Dysfunction of cholesterol sensor SCAP promotes inflammation activation in THP-1 macrophages

Crosstalk occurs between dyslipidemia and chronic inflammation, which are both precipitants of atherosclerosis. Sterol regulatory element binding proteins cleavage-activating protein (SCAP) plays a key role in regulating cholesterol homeostasis. The present study investigated the effects of SCAP dysfunction on the expression of inflammatory cytokines and lipid metabolism in THP-1 macrophages. Intracellular cholesterol content was assessed by Oil Red O staining and quantitative assays. The expression of SCAP, HMGCR, pro-IL-1β and N-SREBP2, p65(N) in the nucleus were examined by real-time quantitative RT-PCR and Western blotting. The level of secretary proteins IL-1β, TNF-α and MCP-1 in the supernatants were determined by ELISA. The translocation of SCAP from the endoplasmic reticulum (ER) to the Golgi was detected by confocal microscopy. Our results demonstrated that over-expression of SCAP significantly increased the expression of HMGCR, pro-IL-1β in the cytoplasm, and mature IL-1β, TNF-α, MCP-1 in the supernatants, while knocking down SCAP dramatically decreased the expression of these molecules. Betulin effectively suppressed the accumulation of intracellular cholesterol in the SCAP over-expressed THP-1 macrophages, but did not affect the expression of inflammatory cytokines, indicating that the pro-inflammatory effect of SCAP was independent of its routine role in regulating cholesterol homeostasis. Furthermore, we investigated the molecular mechanisms mediating the crosstalk between dyslipidemia and inflammatory responses. Knocking down SCAP attenuated LPS-induced IκB phosphorylation and reduced the nuclear level of p65, while over-expression of SCAP increased the nuclear level of p65. Knocking down p65 abolished the proinflammatory effect represented by elevated expression of the inflammatory mediators in the SCAP over-expressed THP-1 macrophages, suggesting that SCAP dysfunction stimulated inflammatory responses via activating the NF-κB signaling pathway. In conclusion, the cholesterol sensor SCAP plays a role in regulating the expression of inflammatory factors such as IL-1β, TNF-α, and MCP-1 in THP-1 macrophages. SCAP mediates the inflammatory response via activating the NF-κB pathway. This new function of SCAP is independent of its role in lipid metabolism.

Electrochemically deposited dendritic poly (methyl orange) nanofilm on metal-carbon-polymer nanocomposite: A novel non-enzymatic electrochemical biosensor for cholesterol

Cholesterol is one of the main biomarkers for atherosclerosis which can lead to the coronary heart and peripheral arterial diseases. Development of non-enzymatic electrochemical biosensors for the measurements of cholesterol over a wide linear concentration range, with high sensitivity and accuracy is challenging. A novel Cu/Ni bimetal-dispersed carbon nanofiber/polymer nanocomposite (BMCP)-based electrode was developed in this study for the measurements of cholesterol. Dendritic nanofibers of poly methyl orange (PMO), which served as the recognition element for cholesterol, were successfully grown over BMCP, using electro-polymerization. Tested using various electrochemical techniques including chronoamperometry and differential pulse voltammetry, the prepared PMO-BMCP biosensor showed a high sensitivity (226.30 μA mM−1 cm−2) and low detection limit (0.002 mg dL−1) over 0.04–600 mg dL−1 concentration range, with remarkable linearity (R2 = 0.999), which were either higher or comparable to most of the cholesterol sensors discussed in literature. The biosensor exhibited good reproducibility and long-time (~8 months) stability of the electrochemical activity. The presence of interfering bioactive agents, namely, glucose, uric acid, creatinine, urea and p-acetamido phenol had negligible effect on the measurement of cholesterol. The proposed material and method described in this study can be used to develop similar non-enzymatic electrochemical biosensors for other bioactive molecules in blood, such as glucose and creatinine.

LSPR- and SPR-Based Fiber-Optic Cholesterol Sensor Using Immobilization of Cholesterol Oxidase Over Silver Nanoparticles Coated Graphene Oxide Nanosheets

Fabrication and characterization of a highly sensitive fiber-optic cholesterol sensor utilizing cholesterol oxidase (ChOx) have been carried out. The operation of the sensor is based on combined phenomenon of localized and propagating surface plasmons. Two different immobilization schemes of enzyme ChOx have been used. In one, the enzyme is entrapped in the hydrogel and in second the enzyme is immobilized over the graphene oxide (GO) nanosheets. The synthesis of GO is confirmed by XRD, TEM, and Raman spectroscopy and the binding between ChOx and GO is verified through the Raman spectroscopy and Fourier transform infrared spectroscopy techniques. Following three types of probes having different configurations are fabricated and compared: 1) enzyme entrapped gel layer over silver coated unclad fiber; 2) enzyme immobilized over silver and GO coated unclad fiber; and 3) enzyme immobilized over silver, GO, and silver nanoparticles coated unclad fiber. The performance of all these probes have been compared in terms of operating range, sensitivity and limit of detection. The sensors have many advantages, such as compact size, modest cost, high sensitivity, high selectivity, and capability of remote sensing.

Polyaniline/MWCNTs/starch modified carbon paste electrode for non-enzymatic detection of cholesterol: application to real sample (cow milk).

Nanocomposite materials are potentially revolutionizing many technologies, including sensors. In this paper, we described the application of "PANI/MWCNTs/Starch" modified carbon paste electrode (PCS-CPE) as a simple and highly sensitive cholesterol sensor. This novel nano-composite material has integrated nano-morphology, where polyaniline could interact effectively with the additives; pi-pi stacking "MWCNTs," and covalently bonded with starch. Specific binding sites (sugar chains), better electro-catalytic properties and fast electron transfer facilitated the oxidation of cholesterol. Fourier transform infrared spectra confirmed the interaction of cholesterol with the composite material. The sensing response of PCS was measured by cyclic voltammetry and chronoamperometry (0.1M PBS-5 used as supporting electrolyte). As the amount of cholesterol increased in the test solution, cyclic voltammograms showed a rise of peak current (cathodic and anodic). Under the normal experimental conditions, the developed sensor exhibited wide linear dynamic range (0.032 to 5mM) (upper limit is due to lack of solubility of cholesterol), high sensitivity (800 μAmM-1cm-2), low detection limit (0.01mM) and shorter response time (within 4-6s). Analytical specificity, selectivity, and sensitivity during cholesterol estimation were compared with the response of some other analytes (ascorbic acid, glucose, l-dopa, urea and lactic acid). This novel sensor was successfully applied to estimate cholesterol in cow milk (used as a model real sample). The sensing platform is highly sensitive and shows a linear response towards cholesterol without using any additionalredox mediator or enzyme, thus this material is extremely promising for the realization of a low-cost integrated cholesterol sensor device. Graphical abstract Cyclic voltammetric response of cholesterol of composite modified carbon paste capillary electrode.

Study of cholesterol derivative and phospholipid (DPPC) mixed film using LB technique and FRET: Design of cholesterol sensor

In this work mixed film behavior of Cholesterol derivative 5α, 6α-Epoxycholestan-3β-ol (Chol) and a Phospholipid named 1,2-Dipalmitoyl-sn-glycero-3-phosphorylcholine (DPPC) have been investigated using Langmuir-Blodgett (LB) technique. Surface pressure-area (π-A) isotherms, UV–vis, and fluorescence spectroscopy and Brewster Angle Microscopy (BAM) studies were carried out for characterizations of the films at air – water interface and solid substrate. π-A isotherms as well as analysis of excess area and Gibb’s free energy suggested interaction between Chol and DPPC in the mixed monolayer. However, interaction between Chol and DPPC balances at Chol mole fraction (XChol) 0.77 resulting in a stable and almost ideally mixed monolayer. BAM investigations give visual evidence of interaction showing change in domain structure/nature in the DPPC-Chol mixed monolayer compared to their pure counterpart. Fluorescence Resonance Energy Transfer (FRET) was employed to sense the presence of Chol in the lipid bilayer film. Acriflavine (Acf) and Rhodamine B (RhB) were used as donor and acceptor respectively. It was found that FRET efficiency linearly changes with Chol concentration in the lipid bilayer. With proper calibration, it may be possible to use this present system under investigation to sense Chol in cell membrane. Proposed sensing system has also been tested using real serum sample.

CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer.

In this study, we used a bioinformatic approach to identify genes whose expression is dysregulated in human prostate cancers. One of the most dramatically downregulated genes identified encodes CYP27A1, an enzyme involved in regulating cellular cholesterol homeostasis. Importantly, lower CYP27A1 transcript levels were associated with shorter disease-free survival and higher tumor grade. Loss of CYP27A1 in prostate cancer was confirmed at the protein level by immunostaining for CYP27A1 in annotated tissue microarrays. Restoration of CYP27A1 expression in cells where its gene was silenced attenuated their growth in vitro and in tumor xenografts. Studies performed in vitro revealed that treatment of prostate cancer cells with 27-hydroxycholesterol (27HC), an enzymatic product of CYP27A1, reduced cellular cholesterol content in prostate cancer cell lines by inhibiting the activation of sterol regulatory-element binding protein 2 and downregulating low-density lipoprotein receptor expression. Our findings suggest that CYP27A1 is a critical cellular cholesterol sensor in prostate cells and that dysregulation of the CYP27A1/27HC axis contributes significantly to prostate cancer pathogenesis. Cancer Res; 77(7); 1662-73. ©2017 AACR.

Fluorescence detection of cholesterol using a nitrogen-doped graphene quantum dot/chromium picolinate complex-based sensor.

Nitrogen-doped graphene quantum dots (N-GQDs), with superior biocompatibility, strong resistance to photobleaching and convenient surface grafting, have sparked a surge of related-bio applications. In this study, combined with chromium picolinate (CrPic), N-GQDs synthesized by a facile hydrothermal approach are used to construct an environmentally-friendly sensor for the detection of cholesterol by exploiting the fluorescence enhancement of N-GQDs/CrPic. Herein, CrPic is grafted on N-GQDs via the linker of cysteamine (Cys), and the fluorescence of the N-GQDs is quenched by photoinduced electron transfer (PET), wherein CrPic functions as an electron donating group and the N-GQDs serves as an electron accepting group. Besides, cholesterol is stimulated to form a favourable complex with N-GQDs/CrPic because CrPic also acts as a potential receptor for cholesterol by strong affinity and π-π interaction, and the fluorescence of N-GQDs/CrPic is enhanced indicating that cholesterol could impede electron transfer from CrPic to the N-GQDs. This N-GQDs/CrPic-based sensor has been successfully applied to selectively determine the concentration of cholesterol with a linear range of 0-520 μM and a limit of detection (LOD) of 0.4 μM. Meanwhile, this present sensing strategy in human serum has acceptable practicability, reproducibility and precision.

Cu-Pt-Bi Nanocomposite Modified Glassy Carbon Electrode for Dual Mode H2O2 and Cholesterol Sensing

In this work, it has been demonstrated that the sequential inclusion of three catalytically active metals (Cu, Pt and Bi) in a glassy carbon (GC) matrix can ascribe a dual role to the trimetallic composite facilitating the oxidation and reduction of H2O2 under physiological conditions. The trimetal based nanosensing platform was constructed by sequential steps which included electrodeposition of Cu, galvanic replacement of Cu by Pt and irreversible adsorption of Bi over Pt. The electrocatalytic activity exhibited by the trimetallic composite was found to depend upon the composition and surface area. The Cu-Pt-Bi nanocomposite modified GC electrode (GC/Cu-Pt-Bi) effectively catalyzed the electrochemical oxidation and reduction of H2O2 at the potential of + 0.25 V and −0.01 V vs NCE (normal calomel electrode) respectively, with fast amperometric response, high sensitivity and low detection limit. Along with these attractive features, the modified electrode also displayed very high specificity to H2O2 with complete elimination of interference from uric acid (UA), ascorbic acid (AA), and glucose. These advantageous characteristics motivated us to build a dual mode cholesterol sensor based on H2O2 transduction by immobilizing cholesterol oxidase (ChOx) on GC/Cu-Pt-Bi. The enzyme modified nanostructured platform provided a highly sensitive and selective sensing of cholesterol coupled with a fast response time and low Km value.

Orthogonal lipid sensors identify transbilayer asymmetry of plasma membrane cholesterol.

Controlled distribution of lipids across various cell membranes is crucial for cell homeostasis and regulation. We developed an imaging method that allows simultaneous in situ quantification of cholesterol in two leaflets of the plasma membrane (PM) using tunable orthogonal cholesterol sensors. Our imaging revealed marked transbilayer asymmetry of PM cholesterol (TAPMC) in various mammalian cells, with the concentration in the inner leaflet (IPM) being ∼12-fold lower than that in the outer leaflet (OPM). The asymmetry was maintained by active transport of cholesterol from IPM to OPM and its chemical retention at OPM. Furthermore, the increase in the IPM cholesterol level was triggered in a stimulus-specific manner, allowing cholesterol to serve as a signaling lipid. We found excellent correlation between the IPM cholesterol level and cellular Wnt signaling activity, suggesting that TAPMC and stimulus-induced PM cholesterol redistribution are crucial for tight regulation of cellular processes under physiological conditions.

Liver X receptors: from cholesterol regulation to neuroprotection-a new barrier against neurodegeneration in amyotrophic lateral sclerosis?

Cholesterol plays a central role in numerous nervous system functions. Cholesterol is the major constituent of myelin sheaths, is essential for synapse and dendrite formation, axon guidance as well as neurotransmission. Among regulators of cholesterol homeostasis, liver X receptors (LXRs), two members of the nuclear receptor superfamily, play a determinant role. LXRs act as cholesterol sensors and respond to high intracellular cholesterol concentration by decreasing plasmatic and intracellular cholesterol content. Beyond their cholesterol-lowering role, LXRs have been proposed as regulators of immunity and anti-inflammatory factors. Dysregulation of cholesterol metabolism combined to neuroinflammatory context have been described in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). ALS is characterized by the progressive loss of motoneurons in the brain and spinal cord, leading to severe paralytic condition and death of patients in a median time of 3years. Motoneuron degeneration is accompanied by chronic neuroinflammatory response, involving microglial and astrocytic activation, infiltration of blood-derived immune cells and release of pro-inflammatory factors. We propose to discuss here the role of LXRs as a molecular link between the central nervous system cholesterol metabolism, neuroinflammation, motoneuron survival and their potential as promising therapeutic candidates for ALS therapy.

Cholesterol-sensing liver X receptors stimulate Th2-driven allergic eosinophilic asthma in mice.

IntroductionLiver X receptors (LXRs) are nuclear receptors that function as cholesterol sensors and regulate cholesterol homeostasis. High cholesterol has been recognized as a risk factor in asthma; however, the mechanism of this linkage is not known.MethodsTo explore the importance of cholesterol homeostasis for asthma, we investigated the contribution of LXR activity in an ovalbumin‐ and a house dust mite‐driven eosinophilic asthma mouse model.ResultsIn both models, airway inflammation, airway hyper‐reactivity, and goblet cell hyperplasia were reduced in mice deficient for both LXRα and LXRβ isoforms (LXRα−/−β−/−) as compared to wild‐type mice. Inversely, treatment with the LXR agonist GW3965 showed increased eosinophilic airway inflammation. LXR activity contributed to airway inflammation through promotion of type 2 cytokine production as LXRα−/−β−/− mice showed strongly reduced protein levels of IL‐5 and IL‐13 in the lungs as well as reduced expression of these cytokines by CD4+ lung cells and lung‐draining lymph node cells. In line herewith, LXR activation resulted in increased type 2 cytokine production by the lung‐draining lymph node cells.ConclusionsIn conclusion, our study demonstrates that the cholesterol regulator LXR acts as a positive regulator of eosinophilic asthma in mice, contributing to airway inflammation through regulation of type 2 cytokine production.

ZnO thin film as MSG for sensitive biosensor

In this paper, we investigate the cholesterol sensors consisting of a mixture of cholesterol oxidase (ChOx) and zinc oxide (ZnO) nanoparticles were grown on ITO/glass substrates by vacuum thermal evaporation method and their sensing characteristics are examined in air. Also, the interest in surface waves appeared due to evanescent waves in the metallic strip grating in sub-wavelength regime. Before testing the transducer with metamaterials lens in the sub-wavelength regime, a simulation of the evanescent wave's formation has been performed at the edge of Ag strips, with thicknesses in the range of micrometers.