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1.
Adv Exp Med Biol ; 1185: 51-55, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884588

RESUMO

The importance of cholesterol as a structural component of photoreceptors and the association between impaired cholesterol homeostasis and age-related macular degeneration (AMD) prompted in the last years a deep investigation of its metabolism in the retina. Here, we focus on the export of cholesterol from intracellular membranes to extracellular acceptors, an active mechanism mediated by the ATP-binding cassette transporters A1 and G1 (ABCA1 and G1) also known as "active cholesterol efflux." Expression of genes involved in this pathway was shown for most retinal cells, while functional in vitro assays focused on the retinal pigment epithelium (RPE) due to availability of cell models. Cell-specific knockout (KO) mice were generated in the past years, and their characterization unveils an important role of the ABCA1/G1 pathway in RPE, rods, and retinal inflammatory cells. The actual involvement of cholesterol efflux in the pathogenesis of AMD still needs to be demonstrated and will help in establishing the scientific rationale for targeting the ABCA1/G1 pathway in retinal diseases.


Assuntos
Colesterol/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico , Degeneração Macular/metabolismo , Camundongos , Camundongos Knockout
2.
Vasc Health Risk Manag ; 15: 309-316, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692533

RESUMO

Experimentally induced injury triggers up-regulation and mobilization of stem cells in Apoe -/- mice that causes accelerated atherosclerosis. Abca1 -/- Abcg1-/- mice have chronic activation of stem cell up-regulation/mobilization and accelerated atherosclerosis. In addition, the Abca1 -/- Abcg1-/- mice have elevation of serum cytokines G-CSF, IL-17 and IL-23, each necessary for stem cell mobilization. IL-17 and IL-23 are elevated in two human illnesses that have cardiovascular (CV) risk independent of traditional risk factors-SLE and psoriasis. Serum G-CSF, which can be elevated in liver disease, predicts major adverse cardiovascular events in humans. These serum cytokine elevations suggest activation of the stem cell mobilization mechanism in humans that results, as in mice, in accelerated atherosclerosis. Efforts to reduce CV disease in these patient populations should include mitigation of the diseases that trigger stem cell mobilization. Since activation of the stem cell up-regulation/mobilization mechanism appears to accelerate human atherosclerosis, use of stem cells as therapy for arterial occlusive disease should distinguish between direct administration of stem cells and activation of the stem cell up-regulation/mobilization mechanism.


Assuntos
Doenças Cardiovasculares/patologia , Movimento Celular , Hepatopatias/patologia , Psoríase/patologia , Células-Tronco/patologia , Transportador 1 de Cassete de Ligação de ATP/deficiência , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/deficiência , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/prevenção & controle , Modelos Animais de Doenças , Progressão da Doença , Humanos , Mediadores da Inflamação/metabolismo , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/terapia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/terapia , Camundongos Knockout para ApoE , Fenótipo , Prognóstico , Psoríase/genética , Psoríase/metabolismo , Psoríase/terapia , Fatores de Risco , Células-Tronco/metabolismo
3.
Mediators Inflamm ; 2019: 6710759, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379468

RESUMO

Epidemiological studies have demonstrated that cardiovascular diseases (CVDs) are the leading cause of death in the world. Atherosclerosis, a kind of chronic vascular disorder related to multiple pathogenic processes, has been reported to be an underlying cause of CVDs. Shexiang Baoxin Pill (SBP) is a traditional Chinese medicine formulation and has been broadly used for the treatment of CVDs in East Asia. However, whether SBP affects the development of atherosclerosis is poorly understood. The aim of this study was to investigate the antiatherosclerotic roles and relevant mechanisms of SBP in apolipoprotein E knockout mice. Our results showed that SBP treatment markedly decreased the size of atherosclerotic plaques of the entire aorta and the aortic sinus. Biochemical analyses indicated that SBP gavage improved oxidative stress in vivo, as seen by the level elevation of SOD, CAT, and GSH and the level reduction of MDA, H2O2, and MPO. Moreover, the concentration of MCP-1, IFN-γ, and IL-17A was reduced, and the content of IL-10 and TGF-ß1 was increased in the serum from SBP-treated mice. We discovered that the expression levels of inflammatory factors including VCAM-1, ICAM-1, IL-6, and IL-2 in the vascular wall of the SBP group were also decreased in comparison with those of the normal saline group. Moreover, we found that SBP alleviated the activation of inflammation-related pathways in the aorta tissue, as seen by the level elevation of Mfn2 and reduced phosphorylation of p38, JNK, and NF-κB. Furthermore, western blot showed that SBP administration reduced the level of SR-A and LOX-1 and elevated the content of LXRα, ABCA1, and ABCG1 in the arterial wall, indicating that SBP was capable of alleviating lipid influx and facilitating lipid efflux. In conclusion, our data suggested that SBP exerted antiatherosclerotic effects via improving inflammation response and inhibiting lipid accumulation.


Assuntos
Aorta/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Transportador 1 de Cassete de Ligação de ATP/sangue , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Animais , Aorta/efeitos dos fármacos , Apolipoproteínas E/sangue , Aterosclerose/sangue , Doenças Cardiovasculares/sangue , Inflamação , Molécula 1 de Adesão Intercelular/sangue , Interleucina-2/sangue , Interleucina-6/sangue , Camundongos , Camundongos Knockout , Estresse Oxidativo/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/sangue
4.
Int J Mol Sci ; 20(11)2019 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-31159502

RESUMO

Several ATP-Binding Cassette (ABC) transporters, including ABCG1 and the related ABCG4, are essential regulators of cellular lipid homeostasis. ABCG1 is expressed ubiquitously and is functional in the context of atherosclerosis. However, ABCG4 is expressed almost exclusively in brain and has been linked to Alzheimer's disease (AD). These transporters are highly regulated post-translationally by E3 ubiquitin ligases, with the ligase NEDD4-1 (Neural precursor cell-expressed developmentally downregulated gene 4) implicated in their protein stability. In this study, we investigated interacting partners of ABCG1 using peptide-mass spectrometry and identified the potential adaptor protein, Alix (apoptosis-linked gene 2-interacting protein X). In this paper, we hypothesized and investigated whether Alix could facilitate the interaction between NEDD4-1 and the ABC transporters. We showed that Alix and NEDD4-1 proteins were co-expressed in several commonly used cell lines. Knockdown of Alix in cells overexpressing ABCG1 or ABCG4 increased transporter protein expression while co-immunoprecipitation experiments showed interaction between NEDD4-1, Alix, and ABC transporters. In summary, we provide evidence that Alix serves as a co-factor for the interaction between the E3-ubiquitin ligase NEDD4-1 and the ABC transporter targets, ABCG1 and ABCG4.


Assuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ciclo Celular/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Animais , Células CHO , Linhagem Celular , Colesterol/metabolismo , Cricetulus , Humanos , Mapas de Interação de Proteínas
5.
J Physiol Pharmacol ; 70(1)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31172973

RESUMO

Obesity is characterised by imbalance in lipid metabolism manifested by high concentrations of circulating triacylglycerols and total cholesterol as well as low high-density lipoprotein (HDL) levels. Abnormalities related to these lipids lead to metabolic complications such as type 2 diabetes, arterial hypertension and cardiovascular disease. Despite extensive research, it is still unclear why a subset of obese subjects develop metabolic syndrome, while others do not. The aim of our work was to assess total and plasma membrane expressions of cholesterol transport proteins: adipocyte ATP-binding cassette A1 (ABCA1), adipocyte ATP-binding cassette G1 (ABCG1), class B scavenger receptor (SR-BI) in visceral and subcutaneous adipose tissue of obese subjects with and without metabolic syndrome. To keep our preliminary study group uniform, we focused on women, who constitute the majority of bariatric patients. The study was performed on 34 patients: 24 morbidly obese women subjected to bariatric surgery, half of whom had metabolic syndrome; and 10 lean subjects undergoing elective laparoscopic cholecystectomy. Total and plasma membrane expressions of cholesterol transport proteins (SR-BI, ABCA1 and ABCG1) were assessed in samples of both visceral and subcutaneous adipose and analysed in relation to other clinical and laboratory parameters. We demonstrated lower plasma membrane expressions of ABCG1 in visceral adipose tissue of obese patients with metabolic syndrome as compared to lean ones. In addition, total ABCG1 expressions in both types of adipose tissue were lower in morbidly obese patients with metabolic syndrome compared to those without metabolic syndrome. Plasma membrane ABCA1 expressions in visceral adipose tissue were lower in the group of morbidly obese patients without metabolic syndrome, compared to lean patients. We did not find any significant differences in SR-BI expressions. Because of ABCG1 is responsible for cholesterol efflux to HDL, reduced plasma membrane expression of ABCG1 in VAT of morbidly obese women with metabolic syndrome may leads to a significantly decreased concentration of HDL in serum. This may be also confirmed by high positive correlation between both parameters.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Tecido Adiposo/metabolismo , Síndrome Metabólica/metabolismo , Obesidade Mórbida/metabolismo , Adulto , Idoso , Colesterol/sangue , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Hipertensão/metabolismo , Pessoa de Meia-Idade , Receptores Depuradores Classe B/metabolismo , Adulto Jovem
6.
J Nutr Sci ; 8: e15, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31037218

RESUMO

Coffee consumption is inversely associated with the risk of non-alcoholic fatty liver disease (NAFLD). A gap in the literature still exists concerning the intestinal mechanisms that are involved in the protective effect of coffee consumption towards NAFLD. In this study, twenty-four C57BL/6J mice were divided into three groups each receiving a standard diet, a high-fat diet (HFD) or an HFD plus decaffeinated coffee (HFD+COFFEE) for 12 weeks. Coffee supplementation reduced HFD-induced liver macrovesicular steatosis (P < 0·01) and serum cholesterol (P < 0·001), alanine aminotransferase and glucose (P < 0·05). Accordingly, liver PPAR- α (P < 0·05) and acyl-CoA oxidase-1 (P < 0·05) as well as duodenal ATP-binding cassette (ABC) subfamily A1 (ABCA1) and subfamily G1 (ABCG1) (P < 0·05) mRNA expressions increased with coffee consumption. Compared with HFD animals, HFD+COFFEE mice had more undigested lipids in the caecal content and higher free fatty acid receptor-1 mRNA expression in the duodenum and colon. Furthermore, they showed an up-regulation of duodenal and colonic zonulin-1 (P < 0·05), duodenal claudin (P < 0·05) and duodenal peptide YY (P < 0·05) mRNA as well as a higher abundance of Alcaligenaceae in the faeces (P < 0·05). HFD+COFFEE mice had an energy intake comparable with HFD-fed mice but starting from the eighth intervention week they gained significantly less weight over time. Data altogether showed that coffee supplementation prevented HFD-induced NAFLD in mice by reducing hepatic fat deposition and metabolic derangement through modification of pathways underpinning liver fat oxidation, intestinal cholesterol efflux, energy metabolism and gut permeability. The hepatic and metabolic benefits induced by coffee were accompanied by changes in the gut microbiota.


Assuntos
Café/metabolismo , Dieta Hiperlipídica/efeitos adversos , Intestinos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Acil-CoA Oxidase/metabolismo , Alanina Transaminase/sangue , Alcaligenaceae , Animais , Glicemia , Colesterol/sangue , Claudinas/metabolismo , Suplementos Nutricionais , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Haptoglobinas/metabolismo , Fígado/patologia , Masculino , Síndrome Metabólica , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/metabolismo , Polifenóis/farmacologia , Precursores de Proteínas/metabolismo , RNA Mensageiro/metabolismo
7.
J Steroid Biochem Mol Biol ; 191: 105377, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31063804

RESUMO

Tumor cells show high avidity for cholesterol in order to support their inherent nature to divide and proliferate. This results in the rewiring of cholesterol homeostatic pathways by influencing not only de novo synthesis but also uptake or efflux pathways of cholesterol. Recent findings have pointed towards the importance of cholesterol efflux in tumor pathogenesis. Cholesterol efflux is the first and foremost step in reverse cholesterol transport and any perturbation in this pathway may lead to the accumulation of intracellular cholesterol, thereby altering the cellular equilibrium. This review addresses the different mechanisms of cholesterol efflux from the cell and highlights their role and regulation in context to tumor development. There are four different routes by which cholesterol can be effluxed from the cell namely, 1) passive diffusion of cholesterol to mature HDL particles, 2) SR-B1 mediated facilitated diffusion, 3) Active efflux to apo A1 via ABCA1 and 4) ABCG1 mediated efflux to mature HDL. These molecular players facilitating cholesterol efflux are engaged in a complex interplay with different signaling pathways. Thus, an understanding of the efflux pathways, their regulation and cross-talk with signaling molecules may provide novel prognostic markers and therapeutic targets to combat the onset of carcinogenesis.


Assuntos
Colesterol/metabolismo , Neoplasias/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico , Difusão , Progressão da Doença , Difusão Facilitada , Homeostase , Humanos , Neoplasias/patologia , Receptores Depuradores Classe B/metabolismo
9.
Mol Immunol ; 107: 21-28, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30639475

RESUMO

BACKGROUND: Lots of studies have demonstrated that immune cells could regulate reverse cholesterol transport (RCT). However, neither T cell receptor (TCR) signalling nor Zeta-chain associated protein 70 (ZAP70) have been demonstrated to be associated with RCT. To investigate this association, we used a ZAP70-deficient Jurkat-derived mutant, P116 cell line, to detect the effect of ZAP70 on RCT and inflammatory response. ZAP70 deficiency improved cholesterol efflux capacity by 14%. Meanwhile, mRNA and proteins expression of RCT regulatory proteins such as ABCA1, ABCG1 and SR-BI were increased in P116 cells. ZAP70-deficiency had no influence on LXR-α and PPAR-γ. Regarding the inflammatory response, the mRNA expression and secretion of pro-atherosclerotic cytokines, TNF-α, IFN-γ, IL-2 and IL-6, were significantly decreased in the ZAP70-deficient cell line. Activation of MAP kinases cascades, as determined by of ERK, JNK and p38 MAPK phosphorylation, were found to be inhibited in the absence of ZAP70. Specific inhibition of ERK, JNK and p38 MAPK activity was also found to decreased TNF-α, IFN-γ, and IL-6 secretion. However, only the ERK inhibition was observed to reduce IL-2 secretion, improve cholesterol efflux capacity and increase expression of ABCA1, ABCG1 and SR-BI without increasing LXR-α and PPAR-γ. Using ChIP assay to detect the binding of LXR-α to LXRE, which promotes the expression of ABCG1, we found that inhibiting ERK improved binding without increasing LXR-α levels. Thus, we speculate that ZAP70-deficiency may improve RCT and decrease the inflammatory response of T cells. Furthermore, these effects are probably achieved via ERK signalling pathway.


Assuntos
Colesterol/metabolismo , Sistema de Sinalização das MAP Quinases , Imunodeficiência Combinada Severa/enzimologia , Imunodeficiência Combinada Severa/metabolismo , Proteína-Tirosina Quinase ZAP-70/deficiência , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transporte Biológico/efeitos dos fármacos , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Células Jurkat , Receptores X do Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteína-Tirosina Quinase ZAP-70/metabolismo
10.
Lipids Health Dis ; 18(1): 2, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30611276

RESUMO

BACKGROUND: ATP-binding cassette (ABC) transporters are involved in a huge range of physiological processes. Mutations in the ABCC6 gene cause pseudoxanthoma elasticum, a metabolic disease with progressive soft tissue calcification. METHODS: The aim of the present study was to analyze gene expression levels of selected ABC transporters associated with cholesterol homeostasis in metabolic active tissues, such as the liver, kidney and white adipose tissue (WAT) of Abcc6-/- mice from an early and late disease stage (six-month-old and 12-month-old mice). RESULTS: The strongest regulation of ABC transporter genes was observed in the liver tissue of six-month-old Abcc6-/- mice. Here, we found a significant increase of mRNA expression levels of phospholipid, bile salt and cholesterol/sterol transporters Abcb1b, Abcb11, Abcg1, Abcg5 and Abcg8. Abcd2 mRNA expression was increased by 3.2-fold in the liver tissue. We observed strong upregulation of Abca3 and Abca1 mRNA expression up to 3.3-fold in kidney and WAT, and a 2-fold increase of Abca9 mRNA in the WAT of six-month-old Abcc6 knockout mice. Gene expression levels of Abcb1b and Abcg1 remained increased in the liver tissue after an age-related disease progression, while we observed lower mRNA expression of Abca3 and Abca9 in the kidney and WAT of 12-month-old Abcc6-/- mice. CONCLUSIONS: These data support previous findings that Abcc6 deficiency leads to an altered gene expression of other ABC transporters depending on the status of disease progression. The increased expression of fatty acid, bile salt and cholesterol/sterol transporters may be linked to an altered cholesterol and lipoprotein metabolism due to a loss of Abcc6 function.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Tecido Adiposo Branco/metabolismo , Rim/metabolismo , Fígado/metabolismo , Pseudoxantoma Elástico/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Subfamília D de Transportador de Cassetes de Ligação de ATP/genética , Subfamília D de Transportador de Cassetes 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/metabolismo , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/deficiência , Transportadores de Cassetes de Ligação de ATP/metabolismo , Tecido Adiposo Branco/patologia , Animais , Ácidos e Sais Biliares/metabolismo , Transporte Biológico , Colesterol/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Regulação da Expressão Gênica , Rim/patologia , Lipoproteínas/genética , Lipoproteínas/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Pseudoxantoma Elástico/metabolismo , Pseudoxantoma Elástico/patologia
11.
Gene ; 689: 24-33, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30528268

RESUMO

AIMS: The previous studies on ABCG1 using genetically modified mice showed inconsistent results on atherosclerosis. The aim of this study was to determine whether accurate target knockout of ABCG1 would result in transcriptional changes of other atherosclerosis-related genes. METHODS: ABCG1 knockout mouse model was obtained by precise gene targeting without affecting non-target DNA sequences in C57BL/6 background. The wildtype C57BL/6 mice were regarded as control group. 12-week-old male mice were used in current study. We performed whole transcriptome analysis on the peripheral blood mononuclear cells obtained from ABCG1 knockout mice (n = 3) and their wildtype controls (n = 3) by RNA-seq. RESULTS: Compared with wildtype group, 605 genes were modified at the time of ABCG1 knockout and expressed differentially in knockout group, including 306 up-regulated genes and 299 down-regulated genes. 54 genes were associated with metabolism regulation, of which 13 were related to lipid metabolism. We also found some other modified genes in knockout mice involved in cell adhesion, leukocyte transendothelial migration and apoptosis, which might also play roles in the process of atherosclerosis. 7 significantly enriched GO terms and 19 significantly enriched KEGG pathways were identified, involving fatty acid biosynthesis, immune response and intracellular signal transduction. CONCLUSIONS: ABCG1 knockout mice exhibited an altered expression of multiple genes related to many aspects of atherosclerosis, which might affect the further studies to insight into the effect of ABCG1 on atherosclerosis with this animal model.


Assuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Aterosclerose/genética , Perfilação da Expressão Gênica , Análise de Sequência de RNA , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Modelos Animais de Doenças , Feminino , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Gravidez , RNA/análise
12.
IUBMB Life ; 71(4): 416-423, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30308094

RESUMO

Vitamin E is an essential molecule for our development and health. It has long been thought that it was absorbed and transported through cellular membranes by a passive diffusion process. However, data obtained during the past 15 years showed that its absorption is actually mediated, at least in part, by cholesterol membrane transporters including the scavenger receptor class B type I (SR-BI), CD36 molecule (CD36), NPC1-like transporter 1 (NPC1L1), and ATP-binding cassettes A1 and G1 (ABCA1 and ABCG1). This review focuses on the absorption process of vitamin E across the enterocyte. A special attention is given to the regulation of this process, including the possible competition with other fat-soluble micronutrients, and the modulation of transporter expressions. Overall, recent results noticeably increased the comprehension of vitamin E intestinal transport, but additional investigations are still required to fully appreciate the mechanisms governing vitamin E bioavailability. © 2018 IUBMB Life, 71(4):416-423, 2019.


Assuntos
Enterócitos/metabolismo , Absorção Intestinal , Vitamina E/farmacocinética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Disponibilidade Biológica , Transporte Biológico , Antígenos CD36/metabolismo , Quilomícrons/metabolismo , Enterócitos/efeitos dos fármacos , Humanos , Proteínas de Membrana Transportadoras/metabolismo
13.
Mol Cell Endocrinol ; 481: 8-13, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30439508

RESUMO

Acyl-ghrelin has various peripheral effects including the potential role in mediating cellular lipid removal and macrophage polarization. Previous reports are contradictory as to how glycaemia and acyl-ghrelin mediates lipid retention and inflammation within individuals with Type 2 diabetes (T2D). Our aim was to explore acyl-ghrelin levels and ghrelin expression in relation to lipid and inflammatory markers within an ex vivo human model, biopsied visceral adipose tissue. Results indicated that acyl-ghrelin was associated with a decline in key lipid homeostasis genes ABCG1 and LXRß expression. Within T2D there was also a down regulation of these genes which was independent of acyl-ghrelin levels. Circulatory pro-inflammatory markers (IL-6 and TNFα) had no association with ghrelin expression nor circulating acyl-ghrelin levels. Anti-inflammatory marker (IL-10) and total antioxidant status (TAOS%) were positively associated with ghrelin expression across samples from all groups combined (total sample cohort) and specifically within the obesity sample cohorts. Data supported the hypothesis that hyperglycaemia and acyl-ghrelin have a regulatory role in lipid retention. Furthermore, that both acyl- and desacyl-ghrelin is responsible for a protective inflammatory response; however this response is diminished in T2D.


Assuntos
Citocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Grelina/metabolismo , Obesidade/patologia , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Biópsia , Feminino , Humanos , Interleucina-10/sangue , Interleucina-6/sangue , Receptores X do Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Obesidade/metabolismo , Fator de Necrose Tumoral alfa/sangue
14.
Biochim Biophys Acta Mol Basis Dis ; 1865(1): 161-180, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30389579

RESUMO

The pathogenesis of Alzheimer's disease (AD) is complex, though the clinical failures of anti-AD candidates targeting Aß production (such as ß- and γ-secretase inhibitors) make people suspect the Aß hypothesis, in which the neurotoxicity of Aß is undoubtedly involved. According to studies, >95% of AD patients with sporadic AD are primarily associated with abnormal Aß clearance. Therefore, drugs that increase Aß clearance are becoming new prospects for the treatment of AD. Here, the novel small molecule OAB-14, designed using bexarotene as the lead compound, significantly alleviated cognitive impairments in amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice after administration for 15 days or 3 months. OAB-14 rapidly cleared 71% of Aß by promoting microglia phagocytosis and increasing IDE and NEP expression. This compound also attenuated the downstream pathological events of Aß accumulation, such as synaptic degeneration, neuronal loss, tau hyperphosphorylation and neuroinflammation in APP/PS1 mice. Moreover, OAB-14 had no significant effect on body weight or liver toxicity after acute and chronic treatment. OAB-14 was well tolerated and its maximum-tolerated dose in mice was >4.0 g/kg. Based on these findings, OAB-14 represents a promising new candidate for AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Bexaroteno/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Presenilina-1/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Secretases da Proteína Precursora do Amiloide , Animais , Apolipoproteínas E/metabolismo , Bexaroteno/administração & dosagem , Bexaroteno/síntese química , Peso Corporal/efeitos dos fármacos , Antígenos CD36/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia , Plasticidade Neuronal/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo
15.
Nat Prod Res ; 33(6): 893-896, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29199477

RESUMO

The phenylpropanoid glucosides from Tadehagi triquetrum were found to be beneficial to glucose and lipid metabolism in vitro. Herein, we investigated the effects of these compounds on oxidised low-density lipoprotein (oxLDL)-induced foam cell formation in RAW264.7 macrophages, aiming to evaluate their potential utility in prevention of atherosclerosis. Our results showed that three out of seven phenylpropanoid glucosides significantly inhibited oxLDL-evoked foam cell formation. These three compounds remarkably inhibited cholesterol influx and enhanced cholesterol efflux. Treatment with compounds 3, 4 and 7 significantly down-regulated the expression of scavenge receptors 1 (SR-1) and cluster of differentiation 36 (CD36) and increased the expression ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1). Analyses of structure-activity relationships revealed that cinnamyl group was the most pivotal group for their activities. This work provided phenomenon that these phenylpropanoid glucosides are effective regulator of cholesterol influx/efflux and may be useful in leading for development of anti-atherosclerotic agents.


Assuntos
Fabaceae/química , Células Espumosas/efeitos dos fármacos , Glucosídeos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Aterosclerose , Transporte Biológico , Antígenos CD36/metabolismo , Linhagem Celular , Colesterol/metabolismo , Regulação para Baixo , Homeostase , Lipoproteínas LDL , Camundongos , Estrutura Molecular , Compostos Fitoquímicos/farmacologia , Células RAW 264.7 , Receptores Depuradores/metabolismo
16.
Life Sci ; 216: 67-74, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30218721

RESUMO

AIMS: The accumulation of lipids in macrophages contributes to the development of atherosclerosis. Cholesterol efflux of lipid-loaded macrophages mediated by ATP binding cassette (ABC) cholesterol transporters, on the other hand, has been shown to attenuate atherosclerosis progression in patients with unknown mechanism. We therefore sought to test the effect of metformin that reduced cardiovascular risk in diabetic patients independent of its hypoglycemia effect on cholesterol transport in murine raw264.7 macrophages. MATERIALS AND METHODS: Mouse raw264.7 macrophages were loaded with Ox-LDL (50 µg/ml) for 24 h before incubated with metformin (15 µM) for 24 h. Foam cell formation was assessed by Oil red staining and BIODIPY fluorescent staining as well as cholesterol-ester quantification by commercial kit. Cholesterol uptake and expression of scavenger receptors were detected by flow-cytometry. Cholesterol efflux capacity was measured by fluorescent plate-reader and ABC transporters were detected by Western Blots. Cytokines were detected by ELISA in supernatants and normalized by cellular lysates. KEY FINDINGS: Our results showed that metformin decreased oxidized low-density lipoprotein (Ox-LDL)-induced cholesterol accumulation and foam cell formation by increasing cholesterol efflux to HDL, which was associated with an upregulation of ABC transporter ABCG-1. Moreover, metformin increased Ox-LDL-impaired IL-10 secretion, an important anti-foam cell cytokine in atherosclerosis. SIGNIFICANCE: Our data highlighted the therapeutic potential of targeting macrophage cholesterol efflux with new or existing drugs for the possible reduction of foam cell formation in the prevention and treatment of diabetes-accelerated atherosclerosis.


Assuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aterosclerose/prevenção & controle , Hipoglicemiantes/farmacologia , Lipoproteínas LDL/administração & dosagem , Metformina/farmacologia , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Colesterol/metabolismo , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , Regulação para Cima/efeitos dos fármacos
17.
Food Funct ; 9(12): 6608-6617, 2018 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-30500001

RESUMO

Three new stilbenoids (1-3) and 16 known stilbenoids (4-6) and cannabinoids (7-19) were isolated from the leaves of hemp (Cannabis sativa L.). The structures of the three new compounds were identified as α,α'-dihydro-3',4,5'-trihydroxy-4'-methoxy-3-isopentenylstilbene (HM1), α,α'-dihydro-3,4',5-trihydroxy-4-methoxy-2,6-diisopentenylstilbene (HM2), and α,α'-dihydro-3',4,5'-trihydroxy-4'-methoxy-2',3-diisopentenylstilbene (HM3) by 1D and 2D NMR spectroscopy, LC-MS, and HRESIMS. The known α,α'-dihydro-3,4',5-trihydroxy-4,5'-diisopentenylstilbene (5) and combretastatin B-2 (6) were isolated for the first time from C. sativa f. sativa. These isolated compounds exhibited cytotoxic effects on human cancer cells via inhibiting the proliferation of cancer cells and inducing cell death. Among them, compounds 4, 5, 10, 12, 13, 15, and 19 displayed broad-spectrum cytotoxicity, and 1, 7, and 11 displayed selectivity in inhibition efficiency on MCF-7 and A549 cells, which suppressed the proliferation of cancer cells significantly by inducing cell death. The effects of compounds 1-3 on improving reverse cholesterol transport (RCT) were evaluated by isotope-tracing and western blotting. Results showed that the three stilbenoids showed a cytotoxicity above 1.0 mg L-1, especially that of HM3. They could improve [3H]-cholesterol efflux from Raw 264.7 macrophages to high density lipoproteins by enhancing the protein expression of ABCG1 and SR-B1, and HM1 and HM2 showed a significant difference compared with fenofibrate at 1.0 mg L-1. The three stilbenoids could also significantly improve the protein expression of ABCA1. Further study on HepG2 cells indicated that they improve the protein expression of LDLR, SR-B1 and CYP7A1, especially that of HM1 and HM3. However, they showed no significant effect on PCSK9. The above results indicated that these stilbenoids may elevate the transfer of cholesterol to hepatocytes by improving the protein expression of SR-B1 and LDLR, and the synthesis of bile acid by increasing the protein expression of CYP7A1. In conclusion, HM1 showed lower cytotoxicity and higher activity in improving the RCT-related protein expression. Our study suggests that it may be explored as a novel lipid-lowering drug and as a beneficial ingredient in health functional foods and pharmaceuticals.


Assuntos
Canabinoides/farmacologia , Cannabis/química , Colesterol/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Estilbenos/farmacologia , 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 , Transporte Biológico/efeitos dos fármacos , Canabinoides/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Estrutura Molecular , Folhas de Planta/química , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Estilbenos/química
18.
Arterioscler Thromb Vasc Biol ; 38(12): 2780-2792, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30571174

RESUMO

Objective- Monocyte-derived foam cells are one of the key players in the formation of atherosclerotic plaques. Adenosine receptors and extracellular adenosine have been demonstrated to modulate foam cell formation. ADK (adenosine kinase) is a major enzyme regulating intracellular adenosine levels, but its functional role in myeloid cells remains poorly understood. To enhance intracellular adenosine levels in myeloid cells, ADK was selectively deleted in novel transgenic mice using Cre-LoxP technology, and foam cell formation and the development of atherosclerotic lesions were determined. Approach and Results- ADK was upregulated in macrophages on ox-LDL (oxidized low-density lipoprotein) treatment in vitro and was highly expressed in foam cells in atherosclerotic plaques. Atherosclerotic mice deficient in ADK in myeloid cells were generated by breeding floxed ADK (ADKF/F) mice with LysM-Cre (myeloid-specific Cre recombinase expressing) mice and ApoE-/- (apolipoprotein E deficient) mice. Mice absent ADK in myeloid cells exhibited much smaller atherosclerotic plaques compared with controls. In vitro assays showed that ADK deletion or inhibition resulted in increased intracellular adenosine and reduced DNA methylation of the ABCG1 (ATP-binding cassette transporter G1) gene. Loss of methylation was associated with ABCG1 upregulation, enhanced cholesterol efflux, and eventually decreased foam cell formation. Conclusions- Augmentation of intracellular adenosine levels through ADK knockout in myeloid cells protects ApoE-/- mice against atherosclerosis by reducing foam cell formation via the epigenetic regulation of cholesterol trafficking. ADK inhibition is a promising approach for the treatment of atherosclerotic diseases.


Assuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adenosina Quinase/deficiência , Aorta/enzimologia , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Epigênese Genética , Células Espumosas/enzimologia , Camundongos Knockout para ApoE , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adenosina Quinase/genética , Animais , Aorta/patologia , Doenças da Aorta/enzimologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Colesterol/metabolismo , Metilação de DNA , Modelos Animais de Doenças , Feminino , Células Espumosas/patologia , Masculino , Camundongos Endogâmicos C57BL , Placa Aterosclerótica , Transdução de Sinais
19.
Life Sci ; 214: 41-50, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30393020

RESUMO

AIMS: Macrophage-derived foam-cell formation plays a crucial role in the development of atherosclerosis, and liver X receptor alpha (LXRα) is a key regulator of lipid metabolism in macrophages. Homocysteine (Hcy) is an independent risk factor of atherosclerosis; however, the regulation of lipid metabolism and role of LXRα induced by Hcy in macrophages is still unknown. The present study aimed to investigate the potential role of Hcy in disordered lipid metabolism and atherosclerotic lesions, especially the effects of Hcy on cholesterol efflux in macrophages and the possible mechanisms. MAIN METHODS: In vitro, lipid accumulation and cholesterol efflux were evaluated in THP-1 macrophages with Hcy intervention. Real-time quantitative PCR and western blot analyses were used to assess mRNA and protein levels. In vivo, atherosclerotic lesions and lipid profiles were evaluated by methionine diet-induced hyperhomocysteinemia (HHcy) in ApoE-/- mice. The LXRα agonist T0901317 was used to verify the role of LXRα in HHcy-accelerated atherosclerosis. KEY FINDINGS: Hcy promoted lipid accumulation and inhibited cholesterol efflux in THP-1 macrophages. HHcy mice showed increased lesion area and lipid accumulation in plaque. Both studies in vitro and in vivo showed decreased expression of ATP binding cassette transporter A1 (ABCA1) and G1 (ABCG1). T0901317 treatment increased ABCA1 and ABCG1 levels; reversed macrophage-derived foam-cell formation in THP-1 macrophages and reduced atherosclerotic lesions in ApoE-/- mice. SIGNIFICANCE: Inhibition of LXRα-mediated ABCA1/ABCG1-dependent cholesterol efflux from macrophages is a novel mechanism in Hcy-accelerated atherosclerosis.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aterosclerose/metabolismo , Homocisteína/metabolismo , Macrófagos/metabolismo , Animais , Aterosclerose/patologia , Linhagem Celular , Colesterol/metabolismo , Células Espumosas/metabolismo , Células Espumosas/patologia , Homocisteína/sangue , Humanos , Hidrocarbonetos Fluorados/farmacologia , Metabolismo dos Lipídeos , Receptores X do Fígado/agonistas , Receptores X do Fígado/metabolismo , Macrófagos/patologia , Masculino , Camundongos Knockout para ApoE , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Sulfonamidas/farmacologia
20.
Theranostics ; 8(18): 4969-4984, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30429880

RESUMO

In advanced atherosclerotic plaques, defective efferocytosis of apoptotic foam cells and decreased cholesterol efflux contribute to lesion progression. In our previous study, we demonstrated that 5-aminolevulinic acid (ALA)-mediated sonodynamic therapy (SDT) could induce foam cells apoptosis via the mitochondrial-caspase pathway. In the current research, we sought to explore ALA-SDT-induced apoptosis of phagocytes and the effects of cholesterol efflux and efferocytosis in advanced apoE-/- mice plaque. Methods: apoE-/- mice fed western diet were treated with ALA-SDT and sacrificed at day 1, day 3, day 7 and day 28 post treatment. THP-1 macrophage-derived foam cells were treated with ALA-SDT. 5 hours later, the supernatant was collected and added to fresh foam cells (phagocytes). Then, the lipid area, efferocytosis, cholesterol efflux, anti-inflammatory reactions and PPARγ-LXRα-ABCA1/ABCG1 pathway were detected in plaque in vivo and in phagocytes in vitro. Results: We found that ALA-SDT induced foam cells apoptosis coupled with efferocytosis and upregulation of Mer tyrosine kinase (MerTK) both in vivo and in vitro. The lipid content in plaque decreased as early as 1 day after ALA-SDT and this tendency persisted until 28 days. The enhancement of phagocytes cholesterol efflux was accompanied by an approximately 40% decrease in free cholesterol and a 24% decrease in total cholesterol in vitro. More importantly, anti-inflammatory factors such as TGFß and IL-10 were upregulated by ALA-SDT treatment. Finally, we found that PPARγ-LXRα-ABCA1/ABCG1 pathway was activated both in vivo and in vitro by ALA-SDT, which could be blocked by PPARγ siRNA. Conclusions: Activation of PPARγ-LXRα-ABCA1/ABCG1 pathway induced by ALA-SDT treatment engages a virtuous cycle that enhances efferocytosis, cholesterol efflux and anti-inflammatory reactions in advanced plaque in vivo and in phagocytes in vitro.


Assuntos
Apoptose , Aterosclerose/terapia , Colesterol/metabolismo , Células Espumosas/efeitos da radiação , Fagocitose/efeitos da radiação , Transdução de Sinais/efeitos da radiação , Ultrassonografia/métodos , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Ácido Aminolevulínico/administração & dosagem , Animais , Aterosclerose/patologia , Modelos Animais de Doenças , Humanos , Receptores X do Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Modelos Teóricos , PPAR gama/metabolismo , Células THP-1 , Resultado do Tratamento , Ondas Ultrassônicas
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