RESUMO
Purpose: Dysregulated cholesterol metabolism is critical in the pathogenesis of AMD. Cellular senescence contributes to the development of numerous age-associated diseases. In this study, we investigated the link between cholesterol burden and the cellular senescence of photoreceptors. Methods: Retinas from rod-specific ATP binding cassette subfamily A member 1 (Abca1) and G member 1 (Abcg1) (Abca1/g1-rod/-rod) knockout mice fed with a high-fat diet were analyzed for the signs of cellular senescence. Real-time quantitative PCR and immunofluorescence were used to characterize the senescence profile of the retina and cholesterol-treated photoreceptor cell line (661W). Inducible elimination of p16(Ink4a)-positive senescent cells (INK-ATTAC) mice or the administration of senolytic drugs (dasatinib and quercetin: D&Q) were used to examine the impact of senolytics on AMD-like phenotypes in Abca1/g1-rod/-rod retina. Results: Increased accumulation of senescent cells as measured by markers of cellular senescence was found in Abca1/g1-rod/-rod retina. Exogenous cholesterol also induced cellular senescence in 661W cells. Selective elimination of senescent cells in Abca1/g1-rod/-rod;INK-ATTAC mice or by administration of D&Q improved visual function, lipid accumulation in retinal pigment epithelium, and Bruch's membrane thickening. Conclusions: Cholesterol accumulation promotes cellular senescence in photoreceptors. Eliminating senescent photoreceptors improves visual function in a model of retinal neurodegeneration, and senotherapy offers a novel therapeutic avenue for further investigation.
Assuntos
Transportador 1 de Cassete de Ligação de ATP , Senescência Celular , Colesterol , Modelos Animais de Doenças , Camundongos Knockout , Degeneração Retiniana , Animais , Camundongos , Senescência Celular/fisiologia , Colesterol/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia , Reação em Cadeia da Polimerase em Tempo Real , Camundongos Endogâmicos C57BL , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/patologia , Células Fotorreceptoras Retinianas Bastonetes/fisiologiaAssuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Colesterol , Colesterol/metabolismo , Colesterol/biossíntese , Animais , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Humanos , Glândulas Suprarrenais/metabolismo , Esteroides/biossíntese , Esteroides/metabolismo , CamundongosRESUMO
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.
Assuntos
Transportador 1 de Cassete de Ligação de ATP , Colesterol , Leucócitos Mononucleares , Receptores X do Fígado , Fígado , Obesidade Mórbida , Receptores para Leptina , Humanos , Obesidade Mórbida/metabolismo , Obesidade Mórbida/cirurgia , Obesidade Mórbida/genética , Masculino , Leucócitos Mononucleares/metabolismo , Feminino , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Adulto , Colesterol/metabolismo , Receptores X do Fígado/metabolismo , Receptores X do Fígado/genética , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Pessoa de Meia-Idade , Fígado/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Transdução de Sinais , Transporte Biológico , Regulação da Expressão Gênica , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genéticaRESUMO
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.
Assuntos
Transportador 1 de Cassete de Ligação de ATP , Colesterol , Células Espumosas , Lipoproteínas LDL , Receptores X do Fígado , Receptores Toll-Like , Humanos , Células Espumosas/metabolismo , Células Espumosas/efeitos dos fármacos , Colesterol/metabolismo , Receptores X do Fígado/metabolismo , Receptores Toll-Like/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/farmacologia , PPAR gama/metabolismo , Células THP-1 , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Lipopolissacarídeos/farmacologia , Receptores Depuradores Classe B/metabolismo , Receptores Depuradores Classe B/genéticaRESUMO
BACKGROUND: ATP-binding cassette subfamily G member 1 is mostly known as a transporter for intracellular cholesterol efflux, and a number of studies indicate that ABCG1 also functions actively in tumor initiation and progression. This review aimed to provide an overall review of how ABCG1 acts in tumor progression. METHOD: A comprehensive searching about ABCG1 and tumor was conducted up to November 2023 using proper keywords through databases including PubMed and Web of Science. RESULT: Overall, ABCG1 plays a crucial role in the development of multiple tumorigenesis. ABCG1 enhances tumor-promoting ability through conferring stem-like properties to cancer cells and mediates chemoresistance in multiple cancers. Additionally, ABCG1 may act as a kinase to phosphorylate downstream molecules and induces tumor growth. In tumor microenvironment, ABCG1 plays a substantial role in immunity response through macrophages to create a tumor-favoring circumstance. CONCLUSION: High expression of ABCG1 is usually associated with poor prognosis, which means ABCG1 may be a potential biomarker for early diagnosis and prognosis of various cancers. ABCG1-targeted therapy may provide a novel treatment for cancer patients.
Assuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Neoplasias , Microambiente Tumoral , Humanos , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Neoplasias/metabolismo , Neoplasias/patologia , Biomarcadores Tumorais/metabolismo , Prognóstico , Animais , Regulação Neoplásica da Expressão GênicaRESUMO
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.
Assuntos
Transportador 1 de Cassete de Ligação de ATP , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Tecido Adiposo , Colesterol , Diabetes Mellitus Tipo 2 , Vesículas Extracelulares , Receptores X do Fígado , Macrófagos , Obesidade , PPAR gama , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Obesidade/metabolismo , Obesidade/genética , Receptores X do Fígado/metabolismo , Receptores X do Fígado/genética , Macrófagos/metabolismo , Colesterol/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Tecido Adiposo/metabolismo , PPAR gama/metabolismo , PPAR gama/genética , Feminino , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Masculino , Pessoa de Meia-Idade , Transporte Biológico , Regulação da Expressão Gênica , Adulto , RNA Mensageiro/metabolismo , RNA Mensageiro/genéticaRESUMO
SCOPE: The cannabidiol (CBD) in hemp oil has important pharmacological activities. Accumulating evidence suggests that CBD is beneficial in the cardiovascular system and has been applied as a health supplement for atherosclerosis. However, the mechanism remains unclear. METHODS AND RESULTS: This study investigates the impact of CBD on foam cell formation, cholesterol homeostasis, and lipid metabolism in macrophages. CBD elevates the levels of peroxisome proliferator-activated receptor gamma (PPARγ) and its associated targets, such as ATP binding transporter A1/G1 (ABCA1/ABCG1), thus reducing foam cell formation, and increasing cholesterol efflux within macrophages. Notably, the upregulation of ABCA1 and ABCG1 expression induced by CBD is found to be attenuated by both a PPARγ inhibitor and PPARγ small interfering RNA (siRNA). Moreover, transfection of PPARγ siRNA results in a decrease in the inhibitory effect of CBD on foam cell formation and promotion of cholesterol efflux. Through lipidomics analysis, the study finds that CBD significantly reverses the enhancement of ceramide (Cer). Correlation analysis indicates a negative association between Cer level and the expression of ABCA1/ABCG1. CONCLUSION: This study confirms that CBD can be an effective therapeutic candidate for atherosclerosis treatment by activating PPARγ, up-regulating ABCA1/ABCG1 expression, and down-regulating Cer level.
Assuntos
Transportador 1 de Cassete de Ligação de ATP , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Canabidiol , Colesterol , Células Espumosas , Homeostase , Metabolismo dos Lipídeos , PPAR gama , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Canabidiol/farmacologia , Colesterol/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , PPAR gama/metabolismo , PPAR gama/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Homeostase/efeitos dos fármacos , Camundongos , Células RAW 264.7 , Ceramidas/metabolismoRESUMO
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.
Assuntos
Colesterol , Diabetes Mellitus Tipo 2 , Receptores X do Fígado , Estado Pré-Diabético , Transdução de Sinais , Humanos , Estado Pré-Diabético/genética , Estado Pré-Diabético/metabolismo , Masculino , Feminino , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Pessoa de Meia-Idade , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Colesterol/metabolismo , Idoso , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Monócitos/metabolismo , Fatores de Risco , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Idoso de 80 Anos ou maisRESUMO
Preclinical studies regarding the potential of liver X receptor (LXR) agonists to inhibit macrophage foam cell formation and the development of atherosclerotic lesions are generally executed in mice fed with Western-type diets enriched in cholesterol and fat. Here, we investigated whether LXR agonism remains anti-atherogenic under dietary conditions with a low basal hepatic lipogenesis rate. Hereto, atherosclerosis-susceptible male apolipoprotein E knockout mice were fed a low-fat diet with or without 10 mg/kg/day LXR agonist T0901317 supplementation for 8 weeks. Importantly, T0901317 significantly stimulated atherosclerosis susceptibility, despite an associated increase in the macrophage gene expression levels of cholesterol efflux transporters ABCA1 and ABCG1. The pro-atherogenic effect of T0901317 coincided with exacerbated hypercholesterolemia, hypertriglyceridemia, and a significant rise in hepatic triglyceride stores and macrophage numbers. Furthermore, T0901317-treated mice exhibited elevated plasma MCP-1 levels and monocytosis. In conclusion, these findings highlight that the pro-atherogenic hepatic effects of LXR agonism are dominant over the anti-atherogenic effects in macrophages in determining the overall atherosclerosis outcome under low-fat diet feeding conditions. A low-fat diet experimental setting, as compared to the commonly used high-fat-diet-based preclinical setup, thus appears more sensitive in uncovering the potential relevance of the off-target liver effects of novel anti-atherogenic therapeutic approaches that target macrophage LXR.
Assuntos
Apolipoproteínas E , Aterosclerose , Benzenossulfonamidas , Fluorocarbonos , Macrófagos , Animais , Masculino , Camundongos , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/prevenção & controle , Aterosclerose/patologia , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Receptores X do Fígado/agonistas , Receptores X do Fígado/metabolismo , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
Impaired cholesterol efflux and/or uptake can influence arterial lipid accumulation leading to atherosclerosis. Here, we report that tripartite motif-containing protein 13 (TRIM13), a RING-type E3 ubiquitin ligase, plays a role in arterial lipid accumulation leading to atherosclerosis. Using molecular approaches and KO mouse model, we found that TRIM13 expression was induced both in the aorta and peritoneal macrophages (pMφ) of ApoE-/- mice in response to Western diet (WD) in vivo. Furthermore, proatherogenic cytokine interleukin-1ß also induced TRIM13 expression both in pMφ and vascular smooth muscle cells. Furthermore, we found that TRIM13 via ubiquitination and degradation of liver X receptor (LXR)α/ß downregulates the expression of their target genes ABCA1/G1 and thereby inhibits cholesterol efflux. In addition, TRIM13 by ubiquitinating and degrading suppressor of cytokine signaling 1/3 (SOCS1/3) mediates signal transducer and activator of transcription 1 (STAT1) activation, CD36 expression, and foam cell formation. In line with these observations, genetic deletion of TRIM13 by rescuing cholesterol efflux and inhibiting foam cell formation protects against diet-induced atherosclerosis. We also found that while TRIM13 and CD36 levels were increased, LXRα/ß, ABCA1/G1, and SOCS3 levels were decreased both in Mφ and smooth muscle cells of stenotic human coronary arteries as compared to nonstenotic arteries. More intriguingly, the expression levels of TRIM13 and its downstream signaling molecules were correlated with the severity of stenotic lesions. Together, these observations reveal for the first time that TRIM13 plays a crucial role in diet-induced atherosclerosis, and that it could be a potential drug target against this vascular lesion.
Assuntos
Aterosclerose , Colesterol , Células Espumosas , Lipoproteínas LDL , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Animais , Humanos , Masculino , Camundongos , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Colesterol/metabolismo , Dieta Ocidental/efeitos adversos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células Espumosas/metabolismo , Células Espumosas/patologia , Lipoproteínas LDL/metabolismo , Receptores X do Fígado/metabolismo , Receptores X do Fígado/genética , Camundongos Knockout para ApoE , Células RAW 264.7 , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/genética , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , UbiquitinaçãoRESUMO
The maintenance of cholesterol homeostasis is essential for central nervous system function. Consequently, factors that affect cholesterol homeostasis are linked to neurological disorders and pathologies. Among them, ATP-binding cassette transporter G1 (ABCG1) plays a significant role in atherosclerosis. However, its role in Alzheimer's disease (AD) is unclear. There is inconsistent information regarding ABCG1's role in AD. It can increase or decrease amyloid ß (Aß) levels in animals' brains. Clinical studies show that ABCG1 is involved in AD patients' impairment of cholesterol efflux capacity (CEC) in the cerebrospinal fluid (CSF). Lower Aß levels in the CSF are correlated with ABCG1-mediated CEC dysfunction. ABCG1 modulates α-, ß-, and γ-secretase activities in the plasma membrane and may affect Aß production in the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) cell compartment. Despite contradictory findings regarding ABCG1's role in AD, this review shows that ABCG1 has a role in Aß generation via modulation of membrane secretases. It is, however, necessary to investigate the underlying mechanism(s). ABCG1 may also contribute to AD pathology through its role in apoptosis and oxidative stress. As a result, ABCG1 plays a role in AD and is a candidate for drug development.
Assuntos
Doença de Alzheimer , Animais , Humanos , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Encéfalo/metabolismo , Colesterol/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismoRESUMO
Dysregulated cholesterol metabolism represents an increasingly recognized feature of autism spectrum disorder (ASD). Children with fetal valproate syndrome caused by prenatal exposure to valproic acid (VPA), an anti-epileptic and mood-stabilizing drug, have a higher incidence of developing ASD. However, the role of VPA in cholesterol homeostasis in neurons and microglial cells remains unclear. Therefore, we examined the effect of VPA exposure on regulation of cholesterol homeostasis in the human microglial clone 3 (HMC3) cell line and the human neuroblastoma cell line SH-SY5Y. HMC3 and SH-SY5Y cells were each incubated in increasing concentrations of VPA, followed by quantification of mRNA and protein expression of cholesterol transporters and cholesterol metabolizing enzymes. Cholesterol efflux was evaluated using colorimetric assays. We found that VPA treatment in HMC3 cells significantly reduced ABCA1 mRNA, but increased ABCG1 and CD36 mRNA levels in a dose-dependent manner. However, ABCA1 and ABCG1 protein levels were reduced by VPA in HMC3. Furthermore, similar experiments in SH-SY5Y cells showed increased mRNA levels for ABCA1, ABCG1, CD36, and 27-hydroxylase with VPA treatment. VPA exposure significantly reduced protein levels of ABCA1 in a dose-dependent manner, but increased the ABCG1 protein level at the highest dose in SH-SY5Y cells. In addition, VPA treatment significantly increased cholesterol efflux in SH-SY5Y, but had no impact on efflux in HMC3. VPA differentially controls the expression of ABCA1 and ABCG1, but regulation at the transcriptional and translational levels are not consistent and changes in the expression of these genes do not correlate with cholesterol efflux in vitro.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Neuroblastoma , Gravidez , Feminino , Criança , Humanos , Ácido Valproico/farmacologia , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/genética , Colesterol/metabolismo , Antígenos CD36/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
Lipid accumulation in macrophages plays an important role in atherosclerosis and is the major cause of atherosclerotic cardiovascular disease. Reducing lipid accumulation in macrophages is an effective therapeutic target for atherosclerosis. Insulin-like growth factor 1 (IGF-1) exerts the anti-atherosclerotic effects by inhibiting lipid accumulation in macrophages. Furthermore, almost all circulating IGF-1 combines with IGF binding proteins (IGFBPs) to activate or inhibit the IGF signaling. However, the mechanism of IGFBPs in macrophage lipid accumulation is still unknown. GEO database analysis showed that among IGFBPS family members, IGFBPL1 has the largest expression change in unstable plaque. We found that IGFBPL1 was decreased in lipid-laden THP-1 macrophages. Through oil red O staining, NBD-cholesterol efflux, liver X receptor α (LXRα) transcription factor and IGR-1 receptor blocking experiments, our results showed that IGFBPL1 inhibits lipid accumulation in THP-1 macrophages through promoting ABCG1-meditated cholesterol efflux, and IGFBPL1 regulates ABCG1 expression and macrophage lipid metabolism through IGF-1R/LXRα pathway. Our results provide a theoretical basis of IGFBPL1 in the alternative or adjunct treatment options for atherosclerosis by reducing lipid accumulation in macrophages.
Assuntos
Aterosclerose , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina , Metabolismo dos Lipídeos , Placa Aterosclerótica , Humanos , Aterosclerose/metabolismo , Transportador 1 de Cassete de Ligação de ATP , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/uso terapêutico , Fator de Crescimento Insulin-Like I/metabolismo , Receptores X do Fígado/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Receptor IGF Tipo 1/metabolismo , Metabolismo dos Lipídeos/genéticaRESUMO
OBJECTIVE: To examine whether participants with different levels of diabetes-related DNA methylation at ABCG1 might respond differently to dietary weight loss interventions with long-term changes in adiposity and body fat distribution. RESEARCH DESIGN AND METHODS: The current study included overweight/obese participants from the POUNDS Lost trial. Blood levels of regional DNA methylation at ABCG1 were profiled by high-resolution methylC-capture sequencing at baseline among 673 participants, of whom 598 were followed up at 6 months and 543 at 2 years. Two-year changes in adiposity and computed tomography-measured body fat distribution were calculated. RESULTS: Regional DNA methylation at ABCG1 showed significantly different associations with long-term changes in body weight and waist circumference at 6 months and 2 years in dietary interventions varying in protein intake (interaction P < 0.05 for all). Among participants assigned to an average-protein (15%) diet, lower baseline regional DNA methylation at ABCG1 was associated with greater reductions in body weight and waist circumference at 6 months and 2 years, whereas opposite associations were found among those assigned to a high-protein (25%) diet. Similar interaction patterns were also observed for body fat distribution, including visceral adipose tissue, subcutaneous adipose tissue, deep subcutaneous adipose tissue, and total adipose tissue at 6 months and 2 years (interaction P < 0.05 for all). CONCLUSIONS: Baseline DNA methylation at ABCG1 interacted with dietary protein intake on long-term decreases in adiposity and body fat distribution. Participants with lower methylation at ABCG1 benefitted more in long-term reductions in body weight, waist circumference, and body fat distribution when consuming an average-protein diet.
Assuntos
Adiposidade , Metilação de DNA , Humanos , Adiposidade/genética , Metilação de DNA/genética , Proteínas Alimentares , Dieta Redutora , Obesidade/genética , Peso Corporal/genética , Circunferência da Cintura , Índice de Massa Corporal , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genéticaRESUMO
Non-small cell lung cancer (NSCLC) is the most prevalent histological type of lung cancer and the leading cause of death globally. Patients with NSCLC have a poor prognosis for various factors, and a late diagnosis is one of them. The DNA methylation of CpG island sequences found in the promoter regions of tumor suppressor genes has recently received attention as a potential biomarker of human cancer. In this study, we report DNA methylation changes of the adenosine triphosphate (ATP)-binding cassette transporter G1 (ABCG1), which belongs to the ATP cassette transporter family in NSCLC patients. Our results demonstrate that ABCG1 is hyper-methylation in NSCLC samples, and these changes are negatively correlated to gene and protein expression. Furthermore, the expression of the ABCG1 gene is significantly associated with the survival time of lung adenocarcinoma (LUAD) patients; however, it did not show a correlation to overall survival (OS) of lung squamous cell carcinoma (LUSC) patients. Notably, we found ABCG1 methylation status at locus cg20214535 is strongly associated with the survival time and consistently observed hyper-methylation in LUAD samples. This novel finding suggests ABCG1 is a potential candidate for targeted therapy in lung cancer via this specific probe. In addition, we illustrate the protein-protein interaction (PPI) of ABCG1 with other proteins and the strong communication of ABCG1 with immune cells.
Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Metilação de DNA , Epigênese Genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismoRESUMO
BACKGROUND: Novel molecular biomarkers for the risk assessment and early detection of coronary heart disease (CHD) are urgently needed for disease prevention. Altered methylation of ATP-binding cassette subfamily G member 1 (ABCG1) has been implicated in CHD but was mostly studied in Caucasians. Exploring the potential relationship between ABCG1 methylation in blood and CHD among the Chinese population would yield valuable insights. METHODS: Peripheral blood samples were obtained from a case-control study (287 CHD patients vs. 277 controls) and a prospective nested case-control study (171 CHD patients and 197 matched controls). DNA extraction and bisulfite-specific PCR amplification techniques were employed for sample processing. Quantitative assessment of methylation levels was conducted using mass spectrometry. Statistical analyses involved the utilization of logistic regression and nonparametric tests. RESULTS: We found hypomethylation of ABCG1 in whole blood was associated with the risk of CHD in both studies, which was enhanced in heart failure (HF) patients, female and younger subjects. When combined with baseline characteristics, altered ABCG1 methylation showed improved predictive effect for differentiating CHD cases, ischemic cardiomyopathy (ICM) cases, younger than 60 years CHD cases, and female CHD cases from healthy controls (area under the curve (AUC) = 0.68, 0.71, 0.74, and 0.73, respectively). CONCLUSIONS: We demonstrated a robust link between ABCG1 hypomethylation in whole blood and CHD risk in the Chinese population and provided novel evidence indicating that aberrant ABCG1 methylation in peripheral blood can serve as an early detection biomarker for CHD patients.
Assuntos
Doença das Coronárias , Metilação de DNA , Feminino , Humanos , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Biomarcadores , Estudos de Casos e Controles , Doença das Coronárias/diagnóstico , Doença das Coronárias/genética , Estudos Prospectivos , Masculino , Pessoa de Meia-Idade , População do Leste Asiático , ChinaRESUMO
Macrophage-derived foam cell formation is critical for the initiation and development of atherosclerosis, which contributes to atherosclerotic cardiovascular disease (ASCVD). Glutathione peroxidase 4 (GPX4), a crucial ferroptosis regulator, protects cells from excessive oxidative stress by neutralizing lipid peroxidation. However, the role of macrophage GPX4 in foam cell formation remains unknown. We reported that oxidized low-density lipoprotein (oxLDL) upregulated GPX4 expression in macrophages. Using the Cre-loxP system, we generated myeloid cell-specific Gpx4 knockout (Gpx4myel-KO ) mice. Bone marrow-derived macrophages (BMDMs) were isolated from WT and Gpx4myel-KO mice and incubated with modified low-density lipoprotein (LDL). We found that Gpx4 deficiency promoted foam cell formation and increased the internalization of modified LDL. Mechanistic studies unveiled that Gpx4 knockout upregulated scavenger receptor type A and LOX-1 expression and downregulated ABCA1 and ABCG1 expression. Collectively, our study lends a novel insight into the role of GPX4 in suppressing macrophage-derived foam cell formation and suggests GPX4 as a promising therapeutic target to interfere with atherosclerosis-related diseases.
Assuntos
Aterosclerose , Células Espumosas , Camundongos , Animais , Células Espumosas/metabolismo , Macrófagos/metabolismo , Lipoproteínas LDL/metabolismo , Receptores Depuradores/metabolismo , Aterosclerose/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismoRESUMO
CONTEXT AND OBJECTIVES: Gestational diabetes mellitus (GDM) is the most common metabolic disorder in pregnancy, and it often leads to adverse pregnancy outcomes and seriously harms the health of mothers and infants. ATP-binding cassette transporter G1 (ABCG1) plays critical roles in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport. This study was designed to explore the relevance of the ABCG1 polymorphisms in the atherometabolic risk in GDM. STUDY DESIGN: The case-control population consists of 1504 subjects. The rs2234715 and rs57137919 single nucleotide polymorphisms (SNPs) were genotyped using PCR and DNA sequencing, and clinical and metabolic parameters were determined. RESULTS: The genotype distributions of the two SNPs showed no difference between the GDM patient and control groups. However, the rs57137919 polymorphism was associated with total cholesterol (TC), and diastolic blood pressure (DBP) levels in patients with GDM. Moreover, subgroup analysis showed that this polymorphism was associated with ApoA1 and DBP levels in overweight/obese patients with GDM, while it was associated with TC, and gestational weight gain (GWG) in non-obese patients with GDM. Meanwhile, the rs2234715 polymorphism was found to be associated with neonatal birth height in non-obese patients with GDM. CONCLUSIONS: The two polymorphisms in the ABCG1 have an influence on atherometabolic traits, GWG, and fetal growth in GDM, depending on the BMI of the patients.
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Diabetes Gestacional , Recém-Nascido , Humanos , Feminino , Gravidez , Diabetes Gestacional/epidemiologia , Gestantes , Transportadores de Cassetes de Ligação de ATP/genética , Resultado da Gravidez , Colesterol , Índice de Massa Corporal , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismoRESUMO
BACKGROUND: Patients with type 2 diabetes mellitus have a high cardiovascular risk due, in part, to abnormalities of high-density lipoprotein mediated cholesterol efflux. The ATP-binding cassette A1 and G1 play a pivotal role in the regulation of cholesterol efflux. However, the regulation of these transporters in type 2 diabetes mellitus remains obscure. OBJECTIVES: This study aimed to investigate the expression of ATP-binding cassette A1 and G1 and their regulation by Liver X receptors in monocyte-derived macrophages in type 2 diabetes mellitus, and to determine whether the alteration of these transporters might affect cholesterol efflux from macrophages. METHODS: Blood was collected from type 2 diabetic patients and healthy controls. Peripheral monocytes were differentiated into macrophages. Quantitative real-time PCR, western blots, and cholesterol efflux assays were performed. The Liver X receptor and Liver X receptor element complex in the ATP-binding cassette G1 gene promoter were detected by electrophoretic mobility supershift assay. RESULTS: Macrophage ATP-binding cassette G1 expression and high density lipoproteininduced cholesterol efflux were significantly reduced in type 2 diabetic patients. However, the mRNA expression of ATP-binding cassette G1 in type 2 diabetic patients was not inhibited by Liver X receptor siRNA and the Liver X receptor- Liver X receptor element complexes remain unchanged similarly. CONCLUSION: The study suggested that the expression of ATP-binding cassette G1 and high density lipoprotein-induced cholesterol efflux in macrophages were reduced in type 2 diabetes mellitus. Impairment of cholesterol efflux and ATP-binding cassette G1 gene expression in type 2 diabetes mellitus might be regulated by a Liver X receptorindependent pathway.
Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Colesterol/metabolismo , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Receptores Nucleares Órfãos/genética , Receptores Nucleares Órfãos/metabolismo , Trifosfato de Adenosina , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genéticaRESUMO
Based on accumulating evidence, cholesterol metabolism dysfunction has been suggested to contribute to the pathophysiological process of traumatic brain injury (TBI) and lead to neurological deficits. As a key transporter of cholesterol that efflux from cells, the ATP-binding cassette (ABC) transporter family exerts many beneficial effects on central nervous system (CNS) diseases. However, there is no study regarding the effects and mechanisms of ABCG1 on TBI. As expected, TBI resulted in the different time-course changes of cholesterol metabolism-related molecules in the injured cortex. Considering ABCG1 is expressed in neuron and glia post-TBI, we generated nestin-specific Abcg1 knockout (Abcg1-KO) mice using the Cre/loxP recombination system. These Abcg1-KO mice showed reduced plasma high-density lipoprotein cholesterol levels and increased plasma lower-density lipoprotein cholesterol levels under the base condition. After TBI, these Abcg1-KO mice were susceptible to cholesterol metabolism turbulence. Moreover, Abcg1-KO exacerbated TBI-induced pyroptosis, apoptosis, neuronal cell insult, brain edema, neurological deficits, and brain lesion volume. Importantly, we found that treating with retinoid X receptor (RXR, the upstream molecule of ABCG1) agonist, bexarotene, in Abcg1-KO mice partly rescued TBI-induced neuronal damages mentioned above and improved functional deficits versus vehicle-treated group. These data show that, in addition to regulating brain cholesterol metabolism, Abcg1 improves neurological deficits through inhibiting pyroptosis, apoptosis, neuronal cell insult, and brain edema. Moreover, our findings demonstrate that the cerebroprotection of Abcg1 on TBI partly relies on the activation of the RXRalpha/PPARgamma pathway, which provides a potential therapeutic target for treating TBI.