RESUMEN
Eriodictyol, a flavonoid distributed in citrus fruits, has been known to exhibit anti-inflammatory activity. In this study, destabilized medial meniscus (DMM)-induced OA model was used to investigate the protective role of eriodictyol on OA. Meanwhile, we used an IL-1ß-stimulated human osteoarthritis chondrocytes model to investigate the anti-inflammatory mechanism of eriodictyol on OA. The production of nitric oxide was detected by Griess reaction. The productions of MMP1, MMP3, and PGE2 were detected by ELISA. The expression of LXRα, ABCA1, PI3K, AKT, and NF-κB were measured by western blot analysis. The results demonstrated that eriodictyol could alleviate DMM-induced OA in mice. In vitro, eriodictyol inhibited IL-1ß-induced NO, PGE2, MMP1, and MMP3 production in human osteoarthritis chondrocytes. Eriodictyol also suppressed the phosphorylation of PI3K, AKT, NF-κB p65, and IκBα induced by IL-1ß. Meanwhile, eriodictyol significantly increased the expression of LXRα and ABCA1. Furthermore, eriodictyol disrupted lipid rafts formation through reducing the cholesterol content. And cholesterol replenishment experiment showed that adding water-soluble cholesterol could reverse the anti-inflammatory effect of eriodictyol. In conclusion, the results indicated eriodictyol inhibited IL-1ß-induced inflammation in human osteoarthritis chondrocytes through suppressing lipid rafts formation, which subsequently inhibiting PI3K/AKT/NF-κB signaling pathway.
Asunto(s)
Condrocitos , Flavanonas , FN-kappa B , Osteoartritis , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Flavanonas/farmacología , Animales , Humanos , Transducción de Señal/efectos de los fármacos , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Ratones , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Osteoartritis/patología , Interleucina-1beta/metabolismo , Receptores X del Hígado/metabolismo , Masculino , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Progresión de la Enfermedad , Modelos Animales de Enfermedad , Antiinflamatorios/farmacología , Óxido Nítrico/metabolismo , Ratones Endogámicos C57BLRESUMEN
Foam cells in atheroma are engorged with lipid droplets (LDs) that contain esters of regulatory lipids whose metabolism remains poorly understood. LD-associated hydrolase (LDAH) has a lipase structure and high affinity for LDs of foam cells. Using knockout and transgenic mice of both sexes, here we show that LDAH inhibits atherosclerosis development and promotes stable lesion architectures. Broad and targeted lipidomic analyzes of primary macrophages and comparative lipid profiling of atheroma identified a broad impact of LDAH on esterified sterols, including natural liver X receptor (LXR) sterol ligands. Transcriptomic analyzes coupled with rescue experiments show that LDAH modulates the expression of prototypical LXR targets and leads macrophages to a less inflammatory phenotype with a profibrotic gene signature. These studies underscore the role of LDs as reservoirs and metabolic hubs of bioactive lipids, and suggest that LDAH favorably modulates macrophage activation and protects against atherosclerosis via lipolytic mobilization of regulatory sterols.
Asunto(s)
Aterosclerosis , Gotas Lipídicas , Receptores X del Hígado , Macrófagos , Ratones Noqueados , Animales , Aterosclerosis/metabolismo , Aterosclerosis/genética , Aterosclerosis/prevención & control , Aterosclerosis/patología , Receptores X del Hígado/metabolismo , Receptores X del Hígado/genética , Ratones , Masculino , Ligandos , Femenino , Gotas Lipídicas/metabolismo , Macrófagos/metabolismo , Esteroles/metabolismo , Células Espumosas/metabolismo , Ratones Transgénicos , Ratones Endogámicos C57BL , Humanos , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patología , Activación de Macrófagos , Esterol EsterasaRESUMEN
The long and very long chain polyunsaturated fatty acids (LC-PUFAs) are preferentially transported by the mother to the fetus. Failure to supply LC-PUFAs is strongly linked with stillbirth, fetal growth restriction, and impaired neurodevelopmental outcomes. However, dietary supplementation during pregnancy is unable to simply reverse these outcomes, suggesting imperfectly understood interactions between dietary fatty acid intake and the molecular mechanisms of maternal supply. Here we employ a comprehensive approach combining untargeted and targeted lipidomics with transcriptional profiling of maternal and fetal tissues in mouse pregnancy. Comparison of wild-type mice with genetic models of impaired lipid metabolism allows us to describe maternal hepatic adaptations required to provide LC-PUFAs to the developing fetus. A late pregnancy-specific, selective activation of the Liver X Receptor signalling pathway dramatically increases maternal supply of LC-PUFAs within circulating phospholipids. Crucially, genetic ablation of this pathway in the mother reduces LC-PUFA accumulation by the fetus, specifically of docosahexaenoic acid (DHA), a critical nutrient for brain development.
Asunto(s)
Ácidos Docosahexaenoicos , Ácidos Grasos Insaturados , Feto , Hígado , Fosfolípidos , Animales , Femenino , Embarazo , Hígado/metabolismo , Fosfolípidos/metabolismo , Ácidos Grasos Insaturados/metabolismo , Ratones , Ácidos Docosahexaenoicos/metabolismo , Feto/metabolismo , Receptores X del Hígado/metabolismo , Receptores X del Hígado/genética , Metabolismo de los Lípidos/genética , Ratones Endogámicos C57BL , Transducción de Señal , Masculino , Lipidómica , Ratones NoqueadosAsunto(s)
Colesterol , Receptores X del Hígado , Estado Prediabético , Transducción de Señal , Humanos , Estado Prediabético/metabolismo , Receptores X del Hígado/metabolismo , Receptores X del Hígado/genética , Colesterol/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Animales , Diabetes Mellitus/metabolismo , Factores de Riesgo , Diabetes Mellitus Tipo 2/metabolismo , RatonesRESUMEN
While the cardiovascular system is a primary target of organophosphorus flame retardants (OPFRs), particularly aryl-OPFRs, it is still exclusive whether the diisodecyl phenyl phosphate (DIDPP), widely used and broadly present in the environment at high concentrations, elicits atherosclerosis effects. Liver X receptors (LXRs) play a direct role in regulating the formation of atherosclerotic lesions. This study was the first to demonstrate that DIDPP acts as an LXRα ligand and functions as an LXRα antagonist with a half-maximal inhibitory concentration of 16.2 µM. We showed that treatment of an in vitro macrophage model with 1 to 10 µM of DIDPP resulted in the downregulation of direct targets of LXRα, namely ABCA1, ABCG1 and SR-B1, thereby leading to a 7.9-13.2 % reduction in cholesterol efflux. This caused dose-dependent, 24.1-43.1 % increases in the staining intensity of foam cells in the macrophage model. This atherosclerotic effect of DIDPP was proposed to be due to its antagonism of LXRα activity, as DIDPP treatment did not alter cholesterol influx. In conclusion, the findings of this study demonstrate that exposure to DIDPP may be a risk factor for atherosclerosis due to the LXRα-antagonistic activity of DIDPP and its ubiquity in the environment.
Asunto(s)
Células Espumosas , Receptores X del Hígado , Receptores X del Hígado/metabolismo , Células Espumosas/efectos de los fármacos , Células Espumosas/metabolismo , Animales , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Colesterol/metabolismo , Organofosfatos/farmacología , Organofosfatos/toxicidad , Ratones , Humanos , Retardadores de Llama/toxicidad , Retardadores de Llama/farmacología , Células RAW 264.7 , Receptores Depuradores de Clase B/metabolismoRESUMEN
Lipopolysaccharide (LPS) acts as a trigger that disrupts metabolic functions and the immune system. While bile acids (BA) have detoxification and anti-inflammatory effects, their role in promoting LPS excretion in broiler chickens remains unclear. This study aimed to investigate the potential of exogenous BA to enhance hepatic clearance of LPS and thereby potentially alleviate LPS-induced liver injury in broiler chickens. Forty-five 21-day-old male broiler chickens were randomly assigned to three groups: the control group, which received daily intraperitoneal injections of a solvent for LPS treatment and a gavage solvent for BA treatment; the LPS group, which received daily intraperitoneal injections of 0.5â¯mg/kg body weight LPS and a gavage solvent for BA treatment; the LPS + BA group, which received daily intraperitoneal injections of 0.5â¯mg/kg body weight LPS and 60â¯mg/kg body weight BA by gavage. BA administered by gavage protected the broiler chickens from increases in liver and spleen indices, systemic inflammatory response, and hepatic damage induced by LPS. Hepatic clearance of LPS was enhanced, as evidenced by decreased serum LPS levels and accelerated excretion into the gallbladder. Additionally, the LPS-induced downregulation of detoxification genes, including those for the lipoprotein receptor and bile acids export pump, was reversed by BA administered by gavage. Furthermore, nuclear transcription factors such as the Farnesoid X receptor (FXR) and Liver X receptor α (LXRα) were enhanced in BA-treated broiler chickens. These findings suggest that BA administration via gavage enhances hepatic LPS clearance through the upregulation of hepatic uptake and efflux proteins, likely mediated by the activation of nuclear transcription factors FXR and LXRα.
Asunto(s)
Ácidos y Sales Biliares , Pollos , Lipopolisacáridos , Hígado , Animales , Lipopolisacáridos/toxicidad , Ácidos y Sales Biliares/metabolismo , Masculino , Hígado/efectos de los fármacos , Hígado/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/veterinaria , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Receptores X del Hígado/metabolismo , Receptores Citoplasmáticos y NuclearesRESUMEN
Euphorbia lathyris L. (EL) is a traditional poisonous herbal medicine used to treat dropsy, ascites, amenorrhea, anuria and constipation. Processing to reduce toxicity of EL is essential for its safe and effective application. However, there is little known regarding the molecular mechanism of reducing toxicity after EL processing. This research aimed to screen the differential markers for EL and PEL, explore the differential mechanisms of inflammatory injury induced by EL and processed EL (PEL) to expound the mechanism of alleviating toxicity after EL processing. The results showed that 15 potential biomarkers, mainly belonging to diterpenoids, were screened to distinguish EL from PEL. EL promoted the expressions of TLR4, NLRP3, NF-κB p65, IL-1ß and TNF-α, increased lipid rafts abundance and promoted TLR4 positioning to lipid rafts. Meanwhile, EL decreased LXRα and ABCA1 expression, and reduced cholesterol efflux. In contrast to EL, the effects of PEL on these indicators were markedly weakened. In addition, Euphorbia factors L1, L2, and L3 affected LXRα, ABCA1, TLR4, NLRP3, NF-κB p65, TNF-α and IL-1ß expression, influenced cholesterol efflux and lipid rafts abundance, and interfered with the colocalization of TLR4 and lipid rafts. The inflammatory injury caused by processed EL was significantly weaker than that caused by crude EL, and reduction of Euphorbia factors L1, L2, and L3 as well as attenuation of inflammatory injury participated in processing-based detoxification of EL. Our results provide valuable insights into the attenuated mechanism of EL processing and will guide future research on the processing mechanism of toxic traditional Chinese medicine.
Asunto(s)
Transportador 1 de Casete de Unión a ATP , Euphorbia , Receptores X del Hígado , Microdominios de Membrana , Receptor Toll-Like 4 , Euphorbia/química , Receptor Toll-Like 4/metabolismo , Receptores X del Hígado/metabolismo , Microdominios de Membrana/efectos de los fármacos , Microdominios de Membrana/metabolismo , Animales , Ratones , Transportador 1 de Casete de Unión a ATP/metabolismo , Inflamación/tratamiento farmacológico , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Células RAW 264.7 , HumanosRESUMEN
Obesity is frequently accompanied by non-alcoholic fatty liver disease (NAFLD). These two diseases are associated with altered lipid metabolism, in which reverse cholesterol transport (LXRα/ABCA1/ABCG1) and leptin response (leptin receptor (Ob-Rb)/Sam68) are involved. The two pathways were evaluated in peripheral blood mononuclear cells (PBMCs) from 86 patients with morbid obesity (MO) before and six months after Roux-en-Y gastric bypass (RYGB) and 38 non-obese subjects. In the LXRα pathway, LXRα, ABCA1, and ABCG1 mRNA expressions were decreased in MO compared to non-obese subjects (p < 0.001, respectively). Ob-Rb was decreased (p < 0.001), whereas Sam68 was increased (p < 0.001) in MO. RYGB did not change mRNA gene expressions. In the MO group, the LXRα pathway (LXRα/ABCA1/ABCG1) negatively correlated with obesity-related variables (weight, body mass index, and hip), inflammation (C-reactive protein), and liver function (alanine-aminotransferase, alkaline phosphatase, and fatty liver index), and positively with serum albumin. In the Ob-R pathway, Ob-Rb and Sam68 negatively correlated with alanine-aminotransferase and positively with albumin. The alteration of LXRα and Ob-R pathways may play an important role in NAFLD development in MO. It is possible that MO patients may require more than 6 months following RYBGB to normalize gene expression related to reverse cholesterol transport or leptin responsiveness.
Asunto(s)
Transportador 1 de Casete de Unión a ATP , Colesterol , Leucocitos Mononucleares , Receptores X del Hígado , Hígado , Obesidad Mórbida , Receptores de Leptina , Humanos , Obesidad Mórbida/metabolismo , Obesidad Mórbida/cirugía , Obesidad Mórbida/genética , Masculino , Leucocitos Mononucleares/metabolismo , Femenino , Receptores de Leptina/genética , Receptores de Leptina/metabolismo , Adulto , Colesterol/metabolismo , Receptores X del Hígado/metabolismo , Receptores X del Hígado/genética , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Persona de Mediana Edad , Hígado/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Transducción de Señal , Transporte Biológico , Regulación de la Expresión Génica , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
Lung type 2 pneumocytes (T2Ps) and alveolar macrophages (AMs) play crucial roles in the synthesis, recycling and catabolism of surfactant material, a lipid/protein fluid essential for respiratory function. The liver X receptors (LXR), LXRα and LXRß, are transcription factors important for lipid metabolism and inflammation. While LXR activation exerts anti-inflammatory actions in lung injury caused by lipopolysaccharide (LPS) and other inflammatory stimuli, the full extent of the endogenous LXR transcriptional activity in pulmonary homeostasis is incompletely understood. Here, using mice lacking LXRα and LXRß as experimental models, we describe how the loss of LXRs causes pulmonary lipidosis, pulmonary congestion, fibrosis and chronic inflammation due to defective de novo synthesis and recycling of surfactant material by T2Ps and defective phagocytosis and degradation of excess surfactant by AMs. LXR-deficient T2Ps display aberrant lamellar bodies and decreased expression of genes encoding for surfactant proteins and enzymes involved in cholesterol, fatty acids, and phospholipid metabolism. Moreover, LXR-deficient lungs accumulate foamy AMs with aberrant expression of cholesterol and phospholipid metabolism genes. Using a house dust mite aeroallergen-induced mouse model of asthma, we show that LXR-deficient mice exhibit a more pronounced airway reactivity to a methacholine challenge and greater pulmonary infiltration, indicating an altered physiology of LXR-deficient lungs. Moreover, pretreatment with LXR agonists ameliorated the airway reactivity in WT mice sensitized to house dust mite extracts, confirming that LXR plays an important role in lung physiology and suggesting that agonist pharmacology could be used to treat inflammatory lung diseases.
Asunto(s)
Homeostasis , Receptores X del Hígado , Macrófagos Alveolares , Neumonía , Surfactantes Pulmonares , Transducción de Señal , Animales , Receptores X del Hígado/metabolismo , Receptores X del Hígado/genética , Surfactantes Pulmonares/metabolismo , Ratones , Neumonía/metabolismo , Neumonía/patología , Macrófagos Alveolares/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Pulmón/metabolismo , Pulmón/patología , Células Epiteliales Alveolares/metabolismo , Asma/metabolismo , Asma/patología , Asma/genética , Colesterol/metabolismo , Metabolismo de los Lípidos , FagocitosisRESUMEN
BACKGROUND: Chronic cerebral hypoperfusion (CCH) has been confirmed as one of the pathogenesis underlying vascular cognitive impairment. A series of pathological changes, including inflammation, oxidative stress, and apoptosis, are involved in this pathophysiology and contribute to cognitive impairment and neuropathological alterations. The traditional Chinese medicine (TCM) of Buqi Huoxue Tongnao (BQHXTN) prescription possesses a remarkable clinical efficacy for treating patients with CCH, but still lacks a scientific foundation for its pharmacological mechanisms. PURPOSE: To investigate the role and underlying mechanism of the effects of BQHXTN on CCH both in vitro and in vivo. METHODS: In this study, we established a two-vessel occlusion (2-VO) induced CCH model in Sprague-Dawley rats, an oxygen-glucose deprivation model in BV2 cells, and a steatosis cell model in L02 cells to reveal the underlying mechanisms of BQHXTN by behavioral test, histopathological analysis and the detection of pro-inflammatory cytokine, apoptotic factors and reactive oxide species. Donepezil hydrochloride and Buyang Huanwu decoction were used as positive drugs. RESULTS: Compared with the 2-VO group, BQHXTN treatment at three doses significantly enhanced the memory and learning abilities in the Y-maze and novel object recognition tests. The hematoxylin-eosin staining indicated that BQHXTN protected against hippocampal injury induced by CCH. Of note, in both in vivo and in vitro experiments, BQHXTN prominently inhibited the production of IL-1ß, TNF-α, cleaved-caspase 3, and iNOS by regulating the PI3K/AKT pathway, consequently exerting anti-inflammatory, anti-apoptotic, and antioxidant effects. Moreover, it provided the first initial evidence that BQHXTN treatment mitigated dyslipidemia by increasing the LXRα/CYP7A1 expression, thereby delaying the neuropathological process. CONCLUSION: In summary, these findings firstly revealed the pharmacodynamics and mechanism of BQHXTN, that is, BQHXTN could alleviate cognitive impairment, neuropathological alterations and dyslipidemia in CCH rats by activating PI3K/AKT and LXRα/CYP7A1 signaling pathways, as well as providing a TCM treatment strategy for CCH.
Asunto(s)
Medicamentos Herbarios Chinos , Receptores X del Hígado , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Transducción de Señal , Animales , Receptores X del Hígado/metabolismo , Medicamentos Herbarios Chinos/farmacología , Transducción de Señal/efectos de los fármacos , Masculino , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas , Modelos Animales de Enfermedad , Apoptosis/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Isquemia Encefálica/tratamiento farmacológico , Línea Celular , Fármacos Neuroprotectores/farmacología , Trastornos Cerebrovasculares/tratamiento farmacológicoRESUMEN
Objective: To investigate the mechanism of Sulfo-N-succinimidyloleate (SSO) regulating lipid metabolism disorder induced by silicon dioxide (SiO(2)) . Methods: In March 2023, Rat alveolar macrophages NR8383 were cultured in vitro and randomly divided into control group (C), SSO exposure group (SSO), SiO(2) exposure group (SiO(2)) and SiO(2)+SSO exposure group (SiO(2)+SSO). NR8383 cells were exposure separately or jointly by SSO and SiO(2) for 36 h to construct cell models. Immunofluorescence and BODIPY 493/ 503 staining were used to detect cluster of differentiation (CD36) and intracellular lipid levels, the protein expression levels of CD36, liver X receptors (LXR), P-mammalian target of rapamycin (P-mTOR) and cholinephosphotransferase 1 (CHPT1) were detected by Western blot, respectively, and lipid metabolomics was used to screen for different lipid metabolites and enrichment pathways. Single-factor ANOVA was used for multi-group comparison, and LSD test was used for pair-to-group comparison. Results: SiO(2) caused the expression of CD36 and P-mTOR to increase (P=0.012, 0.020), the expression of LXR to decrease (P=0.005), and the intracellular lipid level to increase. After SSO treatment, CD36 expression decreased (P=0.023) and LXR expression increased (P=0.000) in SiO(2)+SSO exposure group compared with SiO(2) exposure group. Metabolomics identified 87 different metabolites in the C group and SiO(2) exposure group, 19 different metabolites in the SiO(2) exposure group and SiO(2)+SSO group, and 5 overlaps of different metabolites in the two comparison groups, they are PS (22â¶1/14â¶0), DG (O-16â¶0/18â¶0/0â¶0), PGP (i-13â¶0/i-20â¶0), PC (18â¶3/16â¶0), and Sphinganine. In addition, the differential metabolites of the two comparison groups were mainly concentrated in the glycerophospholipid metabolism and sphingolipid metabolism pathways. The differential gene CHPT1 in glycerophospholipid metabolic pathway was verified, and the expression of CHPT1 decreased after SiO(2) exposure. Conclusion: SSO may improve SiO(2)-induced lipid metabolism disorders by regulating PS (22â¶1/14â¶0), DG (O-16â¶0/18â¶0/0â¶0), PGP (i-13â¶0/i-20â¶0), PC (18â¶3/16â¶0), SPA, glycerophospholipid metabolism and sphingolipid metabolism pathways.
Asunto(s)
Antígenos CD36 , Metabolismo de los Lípidos , Dióxido de Silicio , Animales , Ratas , Dióxido de Silicio/toxicidad , Metabolismo de los Lípidos/efectos de los fármacos , Antígenos CD36/metabolismo , Metabolómica , Trastornos del Metabolismo de los Lípidos/metabolismo , Trastornos del Metabolismo de los Lípidos/inducido químicamente , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Receptores X del Hígado/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , LípidosRESUMEN
Obesity shapes anti-tumor immunity through lipid metabolism; however, the mechanisms underlying how colorectal cancer (CRC) cells utilize lipids to suppress anti-tumor immunity remain unclear. Here, we show that tumor cell-intrinsic ATP6V0A1 drives exogenous cholesterol-induced immunosuppression in CRC. ATP6V0A1 facilitates cholesterol absorption in CRC cells through RAB guanine nucleotide exchange factor 1 (RABGEF1)-dependent endosome maturation, leading to cholesterol accumulation within the endoplasmic reticulum and elevated production of 24-hydroxycholesterol (24-OHC). ATP6V0A1-induced 24-OHC upregulates TGF-ß1 by activating the liver X receptor (LXR) signaling. Subsequently, the release of TGF-ß1 into the tumor microenvironment by CRC cells activates the SMAD3 pathway in memory CD8+ T cells, ultimately suppressing their anti-tumor activities. Moreover, we identify daclatasvir, a clinically used anti-hepatitis C virus (HCV) drug, as an ATP6V0A1 inhibitor that can effectively enhance the memory CD8+ T cell activity and suppress tumor growth in CRC. These findings shed light on the potential for ATP6V0A1-targeted immunotherapy in CRC.
Asunto(s)
Linfocitos T CD8-positivos , Colesterol , Neoplasias Colorrectales , Transducción de Señal , Factor de Crecimiento Transformador beta1 , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Humanos , Animales , Colesterol/metabolismo , Ratones , Línea Celular Tumoral , Factor de Crecimiento Transformador beta1/metabolismo , Memoria Inmunológica , ATPasas de Translocación de Protón Vacuolares/metabolismo , Microambiente Tumoral/inmunología , Receptores X del Hígado/metabolismo , Hidroxicolesteroles/metabolismo , Hidroxicolesteroles/farmacología , Pirrolidinas/farmacología , Proteína smad3/metabolismo , Ratones Endogámicos C57BL , Carbamatos/farmacologíaRESUMEN
Aberrant cholesterol homeostasis is a well-recognized hallmark of cancer and is implicated in metastasis as well as chemotherapeutic resistance, the two major causes of cancer associated mortality. Liver X receptors (LXRs) are the key transcription factors that induce cholesterol efflux via enhancing the expression of ABCA1 and ABCG1. Therefore, a comprehensive analysis of several novel sterols namely ergosta-7,22,24(28)-trien-3ß-ol (Erg1), ergosta-5,22,25-trien-3-ol (Erg2), ergosta-5,7,22,24(28)-tetraen-3ß-ol (Erg3), and ergosta-7,22-dien-3ß-ol (Erg4) as LXR agonists has been performed. Molecular docking studies have shown that these sterols possess higher binding affinities for LXRs as compared to the reference ligands (GW3965 and TO901317) and also formed critical activating interactions. Molecular dynamic (MD) simulations further confirmed that docking complexes made of these sterols possess significant stability. To assess the extent of LXR activation, ABCA1 promoter was cloned into luciferase reporter plasmid and transfected into HCT116 cells. It was observed that treatment with Erg, Erg2 and Erg4 led to a significant LXR activation with an EC50 of 5.64⯵M, 4.83 and 3.03⯵M respectively. Furthermore, a significant increase in mRNA expression of NR1H2 and LXR target genes i.e. ABCA1, ABCG1 and ApoE was observed upon Erg treatment. Flow cytometric analysis have revealed a significant increase in the accumulation of ABCA1 upon Erg treatment. Cytotoxicity studies conducted on colorectal cancer cell and normal epithelial cell line showed that these sterols are selectively toxic towards cancer cells. Taken together, our findings suggests that ergosterol activates LXRs, have significant anticancer activity and could be a likely candidate to manage aberrant cholesterol homeostasis.
Asunto(s)
Antineoplásicos , Neoplasias Colorrectales , Ergosterol , Receptores X del Hígado , Simulación del Acoplamiento Molecular , Humanos , Receptores X del Hígado/agonistas , Receptores X del Hígado/metabolismo , Receptores X del Hígado/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Ergosterol/análogos & derivados , Ergosterol/farmacología , Ergosterol/química , Antineoplásicos/farmacología , Antineoplásicos/química , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Benzoatos/farmacología , Benzoatos/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Colesterol/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Células HCT116 , BencilaminasRESUMEN
Arterial macrophage cholesterol accumulation and impaired cholesterol efflux lead to foam cell formation and the development of atherosclerosis. Modified lipoproteins interact with toll-like receptors (TLR), causing an increased inflammatory response and altered cholesterol homeostasis. We aimed to determine the effects of TLR antagonists on cholesterol efflux and foam cell formation in human macrophages. Stimulated monocytes were treated with TLR antagonists (MIP2), and the cholesterol efflux transporter expression and foam cell formation were analyzed. The administration of MIP2 attenuated the foam cell formation induced by lipopolysaccharides (LPS) and oxidized low-density lipoproteins (ox-LDL) in stimulated THP-1 cells (p < 0.001). The expression of ATP-binding cassette transporters A (ABCA)-1, ABCG-1, scavenger receptor (SR)-B1, liver X receptor (LXR)-α, and peroxisome proliferator-activated receptor (PPAR)-γ mRNA and proteins were increased (p < 0.001) following MIP2 administration. A concentration-dependent decrease in the phosphorylation of p65, p38, and JNK was also observed following MIP2 administration. Moreover, an inhibition of p65 phosphorylation enhanced the expression of ABCA1, ABCG1, SR-B1, and LXR-α. TLR inhibition promoted the cholesterol efflux pathway by increasing the expression of ABCA-1, ABCG-1, and SR-B1, thereby reducing foam cell formation. Our results suggest a potential role of the p65/NF-kB/LXR-α/ABCA1 axis in TLR-mediated cholesterol homeostasis.
Asunto(s)
Transportador 1 de Casete de Unión a ATP , Colesterol , Células Espumosas , Lipoproteínas LDL , Receptores X del Hígado , Receptores Toll-Like , Humanos , Células Espumosas/metabolismo , Células Espumosas/efectos de los fármacos , Colesterol/metabolismo , Receptores X del Hígado/metabolismo , Receptores Toll-Like/metabolismo , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/farmacología , PPAR gamma/metabolismo , Células THP-1 , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Lipopolisacáridos/farmacología , Receptores Depuradores de Clase B/metabolismo , Receptores Depuradores de Clase B/genéticaRESUMEN
Immunoregulatory mechanisms established in the lymphoid organs are vital for preventing autoimmunity. However, the presence of similar mechanisms in non-lymphoid tissues remains unclear. Through transcriptomic and lipidomic analyses, we find a negative association between psoriasis and fatty acid metabolism, as well as Th2 signature. Homeostatic expression of liver X receptor (LXR) and peroxisome proliferator-activated receptor gamma (PPARγ) is essential for maintaining fatty acid metabolism and for conferring resistance to psoriasis in mice. Perturbation of signal transducer and activator of transcription 6 (STAT6) diminishes the homeostatic levels of LXR and PPARγ. Furthermore, mice lacking STAT6, interleukin 4 receptor alpha (IL-4Rα), or IL-13, but not IL-4, exhibit increased susceptibility to psoriasis. Under steady state, innate lymphoid cells (ILCs) are the primary producers of IL-13. In human skin, inhibiting tonic type 2 immunity exacerbates psoriasis-like inflammation and IL-17A, while activating LXR or PPARγ inhibits them. Hence, we propose that tonic type 2 immunity, driven by IL-13-producing ILCs, represents a crucial tissue checkpoint that represses autoimmunity and maintains lipid homeostasis in the skin.
Asunto(s)
Autoinmunidad , Receptores X del Hígado , PPAR gamma , Piel , Animales , Piel/inmunología , Piel/metabolismo , Piel/patología , Humanos , Receptores X del Hígado/metabolismo , Ratones , PPAR gamma/metabolismo , Psoriasis/inmunología , Psoriasis/patología , Psoriasis/metabolismo , Ratones Endogámicos C57BL , Interleucina-13/metabolismo , Factor de Transcripción STAT6/metabolismo , Inmunidad Innata , Masculino , Femenino , Linfocitos/inmunología , Linfocitos/metabolismoRESUMEN
Obesity is a risk factor for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Adipose tissue (AT) extracellular vesicles (EVs) could play a role in obesity and T2DM associated CVD progression via the influence of their specific cargo on gene expression in recipient cells. The aim of this work was to evaluate the effects of AT EVs of patients with obesity with/without T2DM on reverse cholesterol transport (RCT)-related gene expression in human monocyte-derived macrophages (MDMs) from healthy donors. AT EVs were obtained after ex vivo cultivation of visceral and subcutaneous AT (VAT and SAT, respectively). ABCA1, ABCG1, PPARG, LXRß (NR1H2), and LXRα (NR1H3) mRNA levels in MDMs as well as in origine AT were determined by a real-time PCR. T2DM VAT and SAT EVs induced ABCG1 gene expression whereas LXRα and PPARG mRNA levels were simultaneously downregulated. PPARG mRNA levels also decreased in the presence of VAT EVs of obese patients without T2DM. In contrast ABCA1 and LXRß mRNA levels tended to increase with the addition of obese AT EVs. Thus, AT EVs can influence RCT gene expression in MDMs during obesity, and the effects are dependent on T2DM status.
Asunto(s)
Transportador 1 de Casete de Unión a ATP , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1 , Tejido Adiposo , Colesterol , Diabetes Mellitus Tipo 2 , Vesículas Extracelulares , Receptores X del Hígado , Macrófagos , Obesidad , PPAR gamma , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Obesidad/metabolismo , Obesidad/genética , Receptores X del Hígado/metabolismo , Receptores X del Hígado/genética , Macrófagos/metabolismo , Colesterol/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Tejido Adiposo/metabolismo , PPAR gamma/metabolismo , PPAR gamma/genética , Femenino , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Masculino , Persona de Mediana Edad , Transporte Biológico , Regulación de la Expresión Génica , Adulto , ARN Mensajero/metabolismo , ARN Mensajero/genéticaRESUMEN
This study explores the impact of environmental pollutants on nuclear receptors (CAR, PXR, PPARα, PPARγ, FXR, and LXR) and their heterodimerization partner, the Retinoid X Receptor (RXR). Such interaction may contribute to the onset of non-alcoholic fatty liver disease (NAFLD), which is initially characterized by steatosis and potentially progresses to steatohepatitis and fibrosis. Epidemiological studies have linked NAFLD occurrence to the exposure to environmental contaminants like PFAS. This study aims to assess the simultaneous activation of nuclear receptors via perfluorooctanoic acid (PFOA) and RXR coactivation via Tributyltin (TBT), examining their combined effects on steatogenic mechanisms. Mice were exposed to PFOA (10 mg/kg/day), TBT (5 mg/kg/day) or a combination of them for three days. Mechanisms underlying hepatic steatosis were explored by measuring nuclear receptor target gene and lipid metabolism key gene expressions, by quantifying plasma lipids and hepatic damage markers. This study elucidated the involvement of the Liver X Receptor (LXR) in the combined effect on steatosis and highlighted the permissive nature of the LXR/RXR heterodimer. Antagonistic effects of TBT on the PFOA-induced activation of the Pregnane X Receptor (PXR) and Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) were also observed. Overall, this study revealed complex interactions between PFOA and TBT, shedding light on their combined impact on liver health.
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Caprilatos , Fluorocarburos , Compuestos de Trialquiltina , Animales , Compuestos de Trialquiltina/farmacología , Caprilatos/farmacología , Ratones , Fluorocarburos/toxicidad , Fluorocarburos/farmacología , Masculino , Ratones Endogámicos C57BL , Receptores X del Hígado/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Receptores X Retinoide/metabolismo , Hígado Graso/metabolismo , Hígado Graso/inducido químicamente , Hígado Graso/patología , Receptores Citoplasmáticos y Nucleares/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/inducido químicamenteRESUMEN
BACKGROUND: Mycobacterium tuberculosis (MTB) is the causative organism of tuberculosis. Cholesterol is a crucial carbon source required for the survival of MTB in host cells. Transcription factor NR1H3 along with its important target genes ABCA1 and ApoE play important role in removal of extra cholesterol from cells. Changes in the gene expression of NR1H3, ABCA1 and ApoE can affect cholesterol homeostasis and thus the survival of MTB in host cells.Therefore, the present study was designed to analyze the mRNA expression of NR1H3, ABCA1 and ApoE in pulmonary TB (PTB) patients from the population of Punjab, India. METHODS AND RESULTS: In this study, mRNA expression of the transcription factor NR1H3 and its target genes ABCA1 and ApoE was analyzed in 89 subjects, including 41 PTB patients and 48 healthy controls (HCs) by real-time quantitative PCR. It was found that the mRNA expression of both NR1H3 and ABCA1 genes was significantly lower in TB patients than in HCs (p < 0.001). Even after sex-wise stratification of the subjects, mRNA expression of NR1H3 and ABCA1 was found to be down-regulated in both male and female TB patients. No significant difference was observed in expression of ApoE (p = 0.98). CONCLUSIONS: The present study found that the mRNA expression of NR1H3 and ABCA1 is down-regulated in TB patients from Punjab state of India.
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Transportador 1 de Casete de Unión a ATP , Receptores X del Hígado , ARN Mensajero , Tuberculosis Pulmonar , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Transportador 1 de Casete de Unión a ATP/metabolismo , Estudios de Casos y Controles , India , Mycobacterium tuberculosis/genética , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Tuberculosis Pulmonar/genética , Tuberculosis Pulmonar/metabolismo , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismoRESUMEN
Our newly developed menthyl esters of valine and isoleucine exhibit anti-inflammatory properties beyond those of the well-known menthol in macrophages stimulated by lipopolysaccharide (LPS) and in a mouse model of colitis induced by sodium dextran sulfate. Unlike menthol, which acts primarily through the cold-sensitive TRPM8 channel, these menthyl esters displayed unique mechanisms that operate independently of this receptor. They readily penetrated target cells and efficiently suppressed LPS-stimulated tumour necrosis factor-alpha (Tnf) expression mediated by liver X receptor (LXR), a key nuclear receptor that regulates intracellular cholesterol and lipid balance. The menthyl esters showed affinity for LXR and enhanced the transcriptional activity through their non-competitive and potentially synergistic agonistic effect. This effect can be attributed to the crucial involvement of SCD1, an enzyme regulated by LXR, which is central to lipid metabolism and plays a key role in the anti-inflammatory response. In addition, we discovered that the menthyl esters showed remarkable efficacy in suppressing adipogenesis in 3T3-L1 adipocytes at the mitotic clonal expansion stage in an LXR-independent manner as well as in mice subjected to diet-induced obesity. These multiple capabilities of our compounds establish them as formidable allies in the fight against inflammation and obesity, paving the way for a range of potential therapeutic applications.
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Antiinflamatorios , Fármacos Antiobesidad , Receptores X del Hígado , Obesidad , Animales , Ratones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Receptores X del Hígado/metabolismo , Receptores X del Hígado/agonistas , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/uso terapéutico , Adipogénesis/efectos de los fármacos , Ésteres/química , Colitis/tratamiento farmacológico , Colitis/inducido químicamente , Colitis/metabolismo , Humanos , Mentol/farmacología , Ratones Endogámicos C57BL , Lipopolisacáridos , Factor de Necrosis Tumoral alfa/metabolismo , Células 3T3-L1 , Sulfato de Dextran , Adipocitos/metabolismo , Adipocitos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Canales Catiónicos TRPM/metabolismoRESUMEN
BACKGROUNDPreclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) - suggestive of cellular cholesterol accumulation - were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.METHODSMonocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples.RESULTSDuring a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes - ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) - and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D.CONCLUSIONThese data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis.FUNDINGThe MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.