RESUMEN
Background It is known that dietary intake of polyunsaturated fatty acids may improve cardiac function. However, relatively high daily doses are required to achieve sufficient cardiac concentrations of beneficial omega-3 fatty acids. The liver X receptor (LXR) is a nuclear hormone receptor and a crucial regulator of lipid homeostasis in mammals. LXR activation has been shown to endogenously reprogram cellular lipid profiles toward increased polyunsaturated fatty acids levels. Here we studied whether LXR lipid reprogramming occurs in cardiac tissue and exerts cardioprotective actions. Methods and Results Male 129SV mice were treated with the LXR agonist AZ876 (20 µmol/kg per day) for 11 days. From day 6, the mice were injected with the nonselective ß-agonist isoproterenol for 4 consecutive days to induce diastolic dysfunction and subendocardial fibrosis while maintaining systolic function. Treatment with isoproterenol led to a marked impairment of global longitudinal strain and the E/e' ratio of transmitral flow to mitral annular velocity, which were both significantly improved by the LXR agonist. Histological examination showed a significant reduction in isoproterenol-induced subendocardial fibrosis by AZ876. Analysis of the cardiac lipid composition by liquid chromatography-high resolution mass spectrometry revealed a significant increase in cardiac polyunsaturated fatty acids levels and a significant reduction in saturated fatty acids by AZ876. Conclusions The present study provides evidence that the LXR agonist AZ876 prevents subendocardial damage, improves global longitudinal strain and E/e' in a mouse model of isoproterenol-induced cardiac damage, accompanied by an upregulation of cardiac polyunsaturated fatty acids levels. Cardiac LXR activation and beneficial endogenous cardiac lipid reprogramming may provide a new therapeutic strategy in cardiac disease with diastolic dysfunction.
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Compuestos de Anilina/farmacología , Ácidos Grasos/metabolismo , Cardiopatías/prevención & control , Isoproterenol , Miocardio/metabolismo , Tiazoles/farmacología , Animales , Reprogramación Celular , Modelos Animales de Enfermedad , Fibrosis , Cardiopatías/inducido químicamente , Cardiopatías/patología , Receptores X del Hígado/agonistas , Masculino , Ratones , Ratones de la Cepa 129 , Miocardio/patologíaRESUMEN
BACKGROUND: Neuronal excitotoxicity induces a plethora of downstream signaling pathways, resulting in the calcium overload-induced excitotoxic cell death, a well-known phenomenon in cerebrovascular and neurodegenerative disorders. The naturally occurring phytosterol, stigmasterol (ST) is known for its potential role in cholesterol homeostasis and neuronal development. However, the ability of ST to protect against the induced excitotoxicity in hippocampal neurons has not been investigated yet. PURPOSE: The present study aimed to investigate whether ST could protect against hypoxia/reoxygenation (H/R)-induced excitotoxicity in hippocampal neurons. METHODS: After H/R, neurons were initially subjected to trypan blue exclusion assay for the assessment of cell viability. Live staining using fluorescence dyes namely JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide), DCFDA (2',7'-dichlorofluorescein diacetate) and FM1-43 (N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl) were used to measure MMP, ROS and synaptic vesicle pool size. Immunostaining was performed to analyze the expression levels of vesicular glutamate transporter 1 (VGLUT1), N-methyl-D-acetate receptor subunit 2B (GluN2B), LC3BII, p62, and PTEN induced protein kinase 1 (PINK1) in neuron after H/R. Western blotting was carried out to measure the protein expression of GluN2B. The molecular dynamics simulation was employed to elucidate the LXRß agonistic conformation of ST. RESULT: Pre-incubation of neuronal cultures with ST (20 µM) protected against excitotoxicity, and attenuated reactive oxygen species (ROS) generation, double-stranded DNA break, and mitochondrial membrane potential (MMP) loss. ST treatment also resulted in the downregulation of the expressions of VGLUT1 and GluN2B and the reduction of the size of recyclable synaptic vesicle (SV) pool. Like LXRß agonist GW3695, ST suppressed the expression of GluN2B. Furthermore, ST induced mitophagy through upregulating the expressions of LC3BII, p62, and PINK1. The molecular simulation study showed that ST interacted with the ligand binding domain of liver X receptor ß (LXRß), a known binding receptor of ST, through multiple hydrogen bonding. CONCLUSION: Collectively, these findings revealed that ST exhibited a promising neuroprotective effect by regulating both pre- and post-synaptic events following H/R, particularly, attenuation of GluN2B-mediated excitotoxicity and oxidative stress, and induction of mitophagy, and suggested that ST might be a therapeutic promise against ischemic stroke and its associated neurological disorders.
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Receptores X del Hígado/agonistas , Mitofagia/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Daño por Reperfusión/prevención & control , Estigmasterol/farmacología , Animales , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Hipocampo/citología , Hipoxia/tratamiento farmacológico , Hipoxia/fisiopatología , Receptores X del Hígado/química , Receptores X del Hígado/metabolismo , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitofagia/fisiología , Simulación del Acoplamiento Molecular , Neuronas/metabolismo , Neuronas/patología , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Estigmasterol/química , Estigmasterol/metabolismoRESUMEN
BACKGROUND AND AIMS: Hepatitis B virus (HBV) infection is ranked among the top health priorities worldwide. Accumulating evidence suggests that HBV infection and replication are closely associated with liver metabolism. The liver X receptors (LXRs), which belong to the superfamily of nuclear hormone receptors, are important physiological regulators of lipid and cholesterol metabolism. However, the association between the LXR pathway and HBV infection remains largely unclear. APPROACH AND RESULTS: In this study, the antiviral activity of LXR agonists was investigated using multiple HBV cellular models. We observed that in HBV-infected primary human hepatocytes (PHHs), synthetic LXR agonists (T0901317, GW3965, and LXR-623), but not an LXR antagonist (SR9238), potently inhibited HBV replication and gene expression, as demonstrated by substantial reductions in viral RNA, DNA, and antigen production following agonist treatment. However, covalently closed circular DNA (cccDNA) levels were not significantly reduced by the agonists. In addition, no rebound in viral replication was observed after treatment withdrawal, indicating a long-lasting inhibitory effect. These results suggest that LXR agonists decrease the transcriptional activity of cccDNA. In contrast, no significant anti-HBV effect was observed in HepG2-derived cell lines. Interestingly, LXR agonist treatment strongly reduced cholesterol 7α-hydroxylase 1 (CYP7A1) mRNA levels. Knockdown of CYP7A1 gene expression with small interfering RNA inhibited HBV activity in PHHs, suggesting CYP7A1 as a potential factor contributing to the antiviral effects of LXR agonists. CONCLUSIONS: We found that activation of the LXR pathway with synthetic LXR agonists could elicit potent anti-HBV activity in PHHs, possibly through sustained suppression of cccDNA transcription. Our work highlights the therapeutic potential of targeting the LXR pathway for the treatment of chronic HBV infection.
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Antivirales/farmacología , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B/tratamiento farmacológico , Receptores X del Hígado/agonistas , Hígado/metabolismo , Antígenos Virales/genética , Antígenos Virales/aislamiento & purificación , Antivirales/uso terapéutico , Benzoatos/farmacología , Benzoatos/uso terapéutico , Bencilaminas/farmacología , Bencilaminas/uso terapéutico , Células Cultivadas , Colesterol 7-alfa-Hidroxilasa/genética , Colesterol 7-alfa-Hidroxilasa/metabolismo , ADN Viral/aislamiento & purificación , Evaluación Preclínica de Medicamentos , Técnicas de Silenciamiento del Gen , Hepatitis B/virología , Virus de la Hepatitis B/fisiología , Hepatocitos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Hidrocarburos Fluorados/farmacología , Hidrocarburos Fluorados/uso terapéutico , Indazoles/farmacología , Indazoles/uso terapéutico , Hígado/citología , Receptores X del Hígado/antagonistas & inhibidores , Receptores X del Hígado/metabolismo , Cultivo Primario de Células , ARN Viral/aislamiento & purificación , Transducción de Señal/efectos de los fármacos , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Replicación Viral/efectos de los fármacosRESUMEN
Full thickness models (FTMs) are 3D-cultured human skin models that mimic many aspects of native human skin (NHS). However, their stratum corneum (SC) lipid composition differs from NHS causing a reduced skin barrier. The most pronounced differences in lipid composition are a reduction in lipid chain length and increased monounsaturated lipids. The liver-X-receptor (LXR) activates the monounsaturated lipid synthesis via stearoyl-CoA desaturase-1 (SCD-1). Therefore, the aim was to improve the SC lipid synthesis of FTMs by LXR deactivation. This was achieved by supplementing culture medium with LXR antagonist GSK2033. LXR agonist T0901317 was added for comparison. Subsequently, epidermal morphogenesis, lipid composition, lipid organization and the barrier functionality of these FTMs were assessed. We demonstrate that LXR deactivation resulted in a lipid composition with increased overall chain lengths and reduced levels of monounsaturation, whereas LXR activation increased the amount of monounsaturated lipids and led to a reduction in the overall chain length. However, these changes did not affect the barrier functionality. In conclusion, LXR deactivation led to the development of FTMs with improved lipid properties, which mimic the lipid composition of NHS more closely. These novel findings may contribute to design interventions to normalize SC lipid composition of atopic dermatitis patients.
Asunto(s)
Medios de Cultivo/farmacología , Receptores X del Hígado/antagonistas & inhibidores , Cultivo Primario de Células/métodos , Piel/efectos de los fármacos , Sulfonamidas/farmacología , Ceramidas/metabolismo , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/patología , Evaluación Preclínica de Medicamentos/métodos , Ácidos Grasos no Esterificados , Humanos , Hidrocarburos Fluorados/farmacología , Lipogénesis/efectos de los fármacos , Receptores X del Hígado/agonistas , Receptores X del Hígado/metabolismo , Morfogénesis/efectos de los fármacos , Piel/crecimiento & desarrollo , Piel/metabolismo , Estearoil-CoA Desaturasa/metabolismoRESUMEN
Liver X receptors (LXRs) α (NR1H3) and ß (NR1H2) are nuclear receptors that have been involved in the regulation of many physiological processes, principally in the control of cholesterol homeostasis, as well as in the control of the cell death and proliferation balance. These receptors are thus promising therapeutic targets in various pathologies such as dyslipidemia, atherosclerosis, diabetes and/or cancers. These receptors are known to be activated by specific oxysterol compounds. The screening for LXR-specific ligands is a challenging process: indeed, these molecules should present a specificity towards each LXR-isoform. Because some natural products have significant effects in the regulation of the LXR-regulated homeostasis and are enriched in flavonoids, we have decided to test in cell culture the effects of 4 selected flavonoids (galangin, quercetin, apigenin and naringenin) on the modulation of LXR activity using double-hybrid experiments. In silico, molecular docking suggests specific binding pattern between agonistic and antagonistic molecules. Altogether, these results allow a better understanding of the ligand binding pocket of LXRα/ß. They also improve our knowledge about flavonoid mechanism of action, allowing the selection and development of better LXR selective ligands.
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Flavonoides/farmacología , Receptores X del Hígado/agonistas , Receptores X del Hígado/antagonistas & inhibidores , Apigenina/farmacología , Evaluación Preclínica de Medicamentos , Flavanonas/farmacología , Células HeLa , Humanos , Receptores X del Hígado/metabolismo , Simulación del Acoplamiento Molecular , Quercetina/farmacología , Relación Estructura-ActividadRESUMEN
Systemic lupus erythematosus (SLE) constitutes an autoimmune disease characterized by the breakdown of tolerance to self-antigens, sustained production of pathogenic autoantibodies, and damage to multiple organs and tissues. Nanoparticle (NP)-based therapeutics have demonstrated efficacy in attenuating the progression of SLE. However, investigations of nano-drugs that address the crucial initiating factor in the pathogenesis of SLE; e.g., inefficient clearance of apoptotic cells by phagocytes and consequent accumulation of self-antigens, have seldom been reported. Here, an apoptotic cell-mimicking gold nanocage (AuNC)-based nano drug carrier capable of correcting the impaired clearance of apoptotic cells in SLE was rationally designed and generated by conjugating phosphatidylserine (PS) on the surface of liposome-coated AuNCs for liver X receptor (LXR) agonist T0901317 delivery. Notably, PS-lipos-AuNC@T0901317 could efficiently enhance apoptotic cell clearance by elevating the expression of Mer, one of the pivotal phagocytosis-associated receptors on macrophages, resulting in decreased production of anti-dsDNA autoantibodies, reduced inflammatory response, and alleviation of kidney damage in lupus model mice. Additionally, PS-lipos-AuNC could be tracked by photoacoustic imaging for nano drug carrier biodistribution. By addressing the crucial pathogenic factor of SLE, the NP-based delivery system in this study is envisioned to provide a promising strategy to treat this complex and challenging disease.
Asunto(s)
Apoptosis , Sistemas de Liberación de Medicamentos , Oro/administración & dosificación , Hidrocarburos Fluorados/administración & dosificación , Receptores X del Hígado/agonistas , Lupus Eritematoso Sistémico/tratamiento farmacológico , Nanocápsulas/administración & dosificación , Sulfonamidas/administración & dosificación , Animales , Autoanticuerpos/análisis , Citocinas/metabolismo , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Oro/farmacocinética , Hidrocarburos Fluorados/uso terapéutico , Hidrocarburos Fluorados/toxicidad , Liposomas/administración & dosificación , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos MRL lpr , Fosfatidilserinas , Sulfonamidas/uso terapéutico , Sulfonamidas/toxicidad , Distribución Tisular , Tirosina Quinasa c-Mer/biosíntesis , Tirosina Quinasa c-Mer/genéticaRESUMEN
Retinoid X receptor (RXR) ligands have a wide range of beneficial effects in mouse models of Alzheimer's disease (AD). Recently accumulated evidence suggests that early neuroinflammation may be a therapeutic target for AD treatment. We therefore investigated the anti-inflammatory effects of the prenylated flavanoids SPF1 and SPF2, which were previously isolated from root of Sophora tonkinensis and identified as potent ligands for RXR, and potential mechanisms involved. SPF1 and SPF2 efficiently reduced interleukin (IL)-1ß messenger RNA (mRNA) and IL-6 mRNA levels in lipopolysaccharide-stimulated and tumor necrosis factor-α-stimulated RAW264.7 cells, whereas SPF3-which has a structure similar to SPF1 and SPF2 but no RXR ligand activity-did not exhibit such effects. Intriguingly, the liver X receptor (LXR) ligand T0901317 reduced proinflammatory cytokine mRNA levels, and these effects were potentiated by SPF1. With regard to the mechanism underlying the anti-inflammatory effects, SPF1 induced significant amounts of activating transcription factor 3 (ATF3) mRNA and protein, and this effect was potentiated by T0901317. SPF1 also reduced translocation of nuclear factor κB (NF-κB) into nuclei. The production of proinflammatory cytokines was significantly inhibited by SPF1, and this effect was primarily exerted via RXR/LXR heterodimers. The effects of SPF1 may partly depend on the induction of ATF3, which may bind to the p65 subunit of NF-κB, resulting in reduced translocation of NF-κB into nuclei and reduced NF-κB transcription. Although inflammatory effects mediated by RXR/LXR heterodimers have not been thoroughly investigated, the above-described results shed light on the mechanism of the anti-inflammatory effect via RXR/LXR heterodimer.
Asunto(s)
Antiinflamatorios/farmacología , Flavanonas/farmacología , Receptores X del Hígado/agonistas , Receptores X Retinoide/agonistas , Sophora/química , Factor de Transcripción Activador 3/metabolismo , Animales , Hidrocarburos Fluorados/farmacología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Raíces de Plantas/química , Prenilación , Multimerización de Proteína , Células RAW 264.7 , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Sulfonamidas/farmacologíaRESUMEN
Deoxypodophyllotoxin (DPT) is a naturally occurring flavolignan in Anthriscus sylvestris known as cow parsley or wild chervil, and has been reported to have inhibitory effects against several pathological processes including cancer, inflammation and infection. Here, we report the effects of DPT in the fatty liver induced by high fat diet in vivo as well as its regulatory mechanism related with the transcription factor for lipogenic genes such as sterol regulatory element binding protein-1c (SREBP-1c) in vitro. C57BL/6 mice were fed high fat diet for 10 weeks and also orally administrated with DPT for additional 4 weeks. 5 and 10â¯mg/kg of DPT decreased lipid accumulation in the liver induced by high fat diet, as indicated by histological parameters such as Oil Red O staining and hematoxylin & eosin as well as the contents of hepatic triglyceride and cholesterol. In hepatocytes, DPT inhibited the liver X receptor α-mediated SREBP-1c induction and expression of the lipogenic genes, including fatty acid synthase, acetyl-CoA carboxylase and stearoyl-CoA desaturase-1. Moreover, DPT induced AMP-activated protein kinase (AMPK) activation, which has been known to inhibit the expression of SREBP-1c in hepatocyte. Also this compound restored the dysregulation of AMPK and SREBP-1c induced by high fat diet in mice. In conclusion, we demonstrated that DPT significantly inhibited fatty liver by adjusting lipid metabolism coordinated with AMPK activation and SREBP-1c inhibition.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Apiaceae/metabolismo , Hígado/efectos de los fármacos , Podofilotoxina/análogos & derivados , Transducción de Señal/efectos de los fármacos , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Colesterol/metabolismo , Dieta Alta en Grasa , Medicamentos Herbarios Chinos , Células Hep G2 , Humanos , Hidrocarburos Fluorados/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Receptores X del Hígado/agonistas , Receptores X del Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Podofilotoxina/farmacología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Sulfonamidas/farmacología , Triglicéridos/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Activating Liver X receptors (LXRs) represents a promising therapeutic option for dyslipidemia. However, activating LXRα may cause undesired lipogenic effects. Discovery of highly LXRß-selective agonists without LXRα activation were indispensable for dyslipidemia. In this study, in silico approaches were applied to develop highly potent LXRß-selective agonists based on a series of newly reported 3-(4-(2-propylphenoxy)butyl)imidazolidine-2,4-dione-based LXRα/ß dual agonists. Initially, Kohonen and stepwise multiple linear regression SW-MLR were performed to construct models for LXRß agonists and LXRα agonists based on the structural characteristics of LXRα/ß dual agonists, respectively. The obtained LXRß agonist model gave a good predictive ability (R²train = 0.837, R²test = 0.843, Q²LOO = 0.715), and the LXRα agonist model produced even better predictive ability (R²train = 0.968, R²test = 0.914, Q²LOO = 0.895). Also, the two QSAR models were independent and can well distinguish LXRß and LXRα activity. Then, compounds in the ZINC database met the lower limit of structural similarity of 0.7, compared to the 3-(4-(2-propylphenoxy)butyl)imidazolidine-2,4-dione scaffold subjected to our QSAR models, which resulted in the discovery of ZINC55084484 with an LXRß prediction value of pEC50 equal to 7.343 and LXRα prediction value of pEC50 equal to -1.901. Consequently, nine newly designed compounds were proposed as highly LXRß-selective agonists based on ZINC55084484 and molecular docking, of which LXRß prediction values almost exceeded 8 and LXRα prediction values were below 0.
Asunto(s)
Receptores X del Hígado/agonistas , Receptores X del Hígado/metabolismo , Animales , Simulación por Computador , Evaluación Preclínica de Medicamentos , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad CuantitativaRESUMEN
BACKGROUND AND PURPOSE: Agonists for the liver X receptor (LXR) are considered promising therapeutic moieties in cholesterol-driven diseases by promoting cellular cholesterol efflux pathways. However, current clinical application of these agents is hampered by concomitant LXR-induced activation of a lipogenic transcriptional network, leading to hepatic steatosis. Recent studies have suggested that protein arginine methyltransferase 3 (PRMT3) may act as a selective co-activator of LXR activity. Here, we verified the hypothesis that PRMT3 inhibition selectively disrupts the ability of LXR to stimulate lipogenesis while maintaining its capacity to modulate macrophage cholesterol homeostasis. EXPERIMENTAL APPROACH: A combination of the LXR agonist T0901317 and palm oil was administered to C57BL/6 mice to maximally stimulate LXR and PRMT3 activity. PRMT3 activity was inhibited using the allosteric inhibitor SGC707. KEY RESULTS: Treatment with SGC707 did not negatively influence the T0901317/palm oil-induced up-regulation of the cholesterol efflux ATP-binding cassette transporter genes, ABCA1 and ABCG1, in peritoneal cells. In contrast, SGC707 treatment was associated with a significant decrease in the hepatic expression of the lipogenic gene fatty acid synthase (-64%). A similar trend was observed for stearoyl-coenzyme A desaturase and acetyl CoA carboxylase expression (-43%; -56%). This obstruction of lipogenic gene transcription coincided with a significant 2.3-fold decrease in liver triglyceride content as compared with the T0901317 and palm oil-treated control group. CONCLUSION AND IMPLICATIONS: We showed that inhibition of PRMT3 activity by SGC707 treatment selectively impairs LXR-driven transcription of hepatic lipogenic genes, while the positive effect of LXR stimulation on macrophage cholesterol efflux pathways is maintained.
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Isoquinolinas/farmacología , Lipogénesis/efectos de los fármacos , Receptores X del Hígado/genética , Hígado/efectos de los fármacos , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Transportador 1 de Casete de Unión a ATP/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Animales , Colesterol/sangre , Hidrocarburos Fluorados/farmacología , Lipogénesis/genética , Hígado/metabolismo , Receptores X del Hígado/agonistas , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Aceite de Palma/farmacología , Sulfonamidas/farmacología , Transcripción Genética/efectos de los fármacos , Triglicéridos/sangreRESUMEN
The generation of CD138+ phagocytic macrophages with an alternative (M2) phenotype that clear apoptotic cells from tissues is defective in lupus. Liver X receptor-alpha (LXRα) is an oxysterol-regulated transcription factor that promotes reverse cholesterol transport and alternative (M2) macrophage activation. Conversely, hypoxia-inducible factor 1-α (HIF1α) promotes classical (M1) macrophage activation. The objective of this study was to see if lupus can be treated by enhancing the generation of M2-like macrophages using LXR agonists. Peritoneal macrophages from pristane-treated mice had an M1 phenotype, high HIFα-regulated phosphofructokinase and TNFα expression (quantitative PCR, flow cytometry), and low expression of the LXRα-regulated gene ATP binding cassette subfamily A member 1 (Abca1) and Il10 vs. mice treated with mineral oil, a control inflammatory oil that does not cause lupus. Glycolytic metabolism (extracellular flux assays) and Hif1a expression were higher in pristane-treated mice (M1-like) whereas oxidative metabolism and LXRα expression were higher in mineral oil-treated mice (M2-like). Similarly, lupus patients' monocytes exhibited low LXRα/ABCA1 and high HIF1α vs. CONTROLS: The LXR agonist T0901317 inhibited type I interferon and increased ABCA1 in lupus patients' monocytes and in murine peritoneal macrophages. In vivo, T0901317 induced M2-like macrophage polarization and protected mice from diffuse alveolar hemorrhage (DAH), an often fatal complication of lupus. We conclude that end-organ damage (DAH) in murine lupus can be prevented using an LXR agonist to correct a macrophage differentiation abnormality characteristic of lupus. LXR agonists also decrease inflammatory cytokine production by human lupus monocytes, suggesting that these agents may be have a role in the pharmacotherapy of lupus.
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Hidrocarburos Fluorados/farmacología , Receptores X del Hígado/agonistas , Macrófagos Peritoneales/efectos de los fármacos , Sulfonamidas/farmacología , Animales , Polaridad Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Hemorragia/prevención & control , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/metabolismo , Macrófagos Peritoneales/patología , Macrófagos Peritoneales/fisiología , Ratones , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Terpenos/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Liver X receptors (LXR) are important transcription factors involved in the regulation of carbohydrate and lipid metabolism. Recently, we described LXR receptors expression in the hypothalamus but their function in this brain area remains unknown. Here, we evaluated the function of LXR on the expression of factors produced in the hypothalamus in vitro and in vivo by Western blotting and immunocytochemistry. More precisely we studied the expression of GnRH and GHRH, αMSH and NPY in male Sprague-Dawley rats. The effects of two synthetic LXR agonists, T0901317 and GW3965, were first tested in vitro. Hypothalamic explants were treated with either T0901317 or GW3965 (10µM) for 2, 4, 6 and 8h. As a positive control the cholesterol ABCA1 and glucose GLUT2 transporters were used. No changes were observed in the expression of the factors evaluated in vitro. The effects of the LXR agonists were then tested in vivo. Rats were injected ICV into the third ventricle with either T0901317 or GW3965 (2.5µg/5µL ICV) and after 3.5h or 24h the hypothalami were dissected out and rapidly frozen for analysis. αMSH and GnRH expression was significantly increased after 3.5h of T0901317 treatment. Anterior/posterior hypothalamic ratio increases for αMSH expression and decreases for GnRH expression after 24h of LXR activation. Altogether these results show that LXR activation affects the expression of GnRH and αMSH, suggesting that LXR in the hypothalamus is capable of modulating hypothalamic responses related to appetite, sexual behavior and reproductive functions.
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Hormona Liberadora de Gonadotropina/biosíntesis , Hipotálamo/metabolismo , Receptores X del Hígado/metabolismo , alfa-MSH/biosíntesis , Animales , Expresión Génica , Hormona Liberadora de Gonadotropina/genética , Hidrocarburos Fluorados/farmacología , Hipotálamo/efectos de los fármacos , Receptores X del Hígado/agonistas , Masculino , Ratas , Ratas Sprague-Dawley , Sulfonamidas/farmacología , alfa-MSH/genéticaAsunto(s)
Dislipidemias/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Transporte Biológico , Colesterol/sangre , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , HDL-Colesterol/administración & dosificación , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Suplementos Dietéticos , Dislipidemias/sangre , Mutación con Ganancia de Función , Humanos , Hipolipemiantes/farmacología , Receptores X del Hígado/agonistas , Niacina/uso terapéutico , Oligorribonucleótidos Antisentido/uso terapéutico , Inhibidores de PCSK9 , Proproteína Convertasa 9/sangre , Proproteína Convertasa 9/genética , Proteínas Recombinantes/administración & dosificaciónRESUMEN
UNLABELLED: Wilson disease (WD) is a hepatoneurological disorder caused by mutations in the copper-transporter, ATP7B. Copper accumulation in the liver is a hallmark of WD. Current therapy is based on copper chelation, which decreases the manifestations of liver disease, but often worsens neurological symptoms. We demonstrate that in Atp7b(-/-) mice, an animal model of WD, liver function can be significantly improved without copper chelation. Analysis of transcriptional and metabolic changes in samples from WD patients and Atp7b(-/-) mice identified dysregulation of nuclear receptors (NRs), especially the liver X receptor (LXR)/retinoid X receptor heterodimer, as an important event in WD pathogenesis. Treating Atp7b(-/-) mice with the LXR agonist, T0901317, ameliorated disease manifestations despite significant copper overload. Genetic markers of liver fibrosis and inflammatory cytokines were significantly decreased, lipid profiles normalized, and liver function and histology were improved. CONCLUSIONS: The results demonstrate the major role of an altered NR function in the pathogenesis of WD and suggest that modulation of NR activity should be explored as a supplementary approach to improving liver function in WD. (Hepatology 2016;63:1828-1841).
Asunto(s)
Degeneración Hepatolenticular/tratamiento farmacológico , Hidrocarburos Fluorados/uso terapéutico , Metabolismo de los Lípidos/efectos de los fármacos , Receptores X del Hígado/agonistas , Hígado/efectos de los fármacos , Sulfonamidas/uso terapéutico , Adenosina Trifosfatasas/genética , Animales , Proteínas de Transporte de Catión/genética , Cobre/metabolismo , ATPasas Transportadoras de Cobre , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Degeneración Hepatolenticular/genética , Humanos , Hidrocarburos Fluorados/farmacología , Hígado/metabolismo , Pruebas de Función Hepática , Receptores X del Hígado/metabolismo , Ratones Noqueados , Receptores X Retinoide/metabolismo , Sulfonamidas/farmacologíaRESUMEN
Liver X receptor ß (LXRß) has been a new target in the treatment of hyperlipemia, which was related to the cholesterol homeostasis. In this study, the quantitative pharmacophores were constructed by 3D-QSAR pharmacophore (Hypogen) method based on the LXRß agonists. The optimal pharmacophore model containing one hydrogen bond acceptor, two hydrophobics and one ring aromatic was obtained based on five assessment indictors, including the correlation between predicted value and experimental value of the compounds in training set (correlation), Δcost of the models (Δcost), hit rate of active compounds (HRA), identification of effectiveness index (IEI) and comprehensive evaluation index (CAI). And the values of the five assessment indicators were 0.95, 128.65, 84.44%, 2.58 and 2.18 respectively. The best model as a query to screen the traditional Chinese medicine database (TCMD), a list of 309 compounds was obtained andwere then refined using Libdock program. Finally, based on the screening rules of the Libdock score of initial compound and the key interactions between initial compound and receptor, four compounds, demethoxycurcumin, isolicoflavonol, licochalcone E and silydianin, were selected as potential LXRß agonists. The molecular simulation methods were high-efficiency and time-saving to obtainthe potential LXRß agonists, which could provide assistance for further researchingnovel anti-hyperlipidemia drugs.