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1.
Life Sci ; 241: 117118, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31790686

RESUMO

AIMS: Acute pancreatitis (AP) is usually complicated with multiple organ insufficiency, including renal injury. Hyperlipidemia is regarded as a risk factor to induce AP. High-fat diet-induced hyperlipidemic pancreatitis (HP) increased nowadays and showed more severe symptoms and complications than other AP. However, detailed mechanisms or mediators involved in HP complicated with acute renal injury were less studied. Here, we aimed to study how miR-214 expresses in the HP and whether miR-214 has functions to regulate pathological kidney damages induced by HP. MAIN METHODS: Sprague-Dawley rats were adopted to establish HP model complicated with acute renal injury through long-term high-fat diet and sodium taurocholic injection. Models were injected with LV-rno-miR-214-3p or LV-anti-rno-miR-214-3p to exogenously regulate miR-214-3p to study its impacts on HP via a series of molecular and histological experiments. KEY FINDINGS: MiR-214-3p was found to be up-regulated in the kidney, pancreas and serum of HP rats and also could intensify the pathological alterations, kidney and pancreas damages and fibrosis induced by HP. Inflammatory response in HP was enhanced when miR-214-3p was overexpressed. Besides, miR-214-3p up-regulation was showed to inhibit PTEN expression but increased P-Akt levels in the HP kidney, which might be a possible mechanism to induce severe symptoms of pancreatitis. Knockdown of miR-214-3p showed opposite effects. SIGNIFICANCE: MiR-214-3p is indicated to exacerbate the tissue damages and inflammatory response caused by HP complicated with acute renal injury, which may provide a novel therapeutic perspective targeting miR-214-3p to treat HP with acute renal injury.


Assuntos
Lesão Renal Aguda/genética , Hiperlipidemias/complicações , MicroRNAs/genética , Pancreatite/complicações , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Amilases/sangue , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hiperlipidemias/genética , Rim/patologia , Lipídeos/sangue , Lipídeos/genética , Masculino , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Pancreatite/genética , Pancreatite/patologia , Ratos Sprague-Dawley
2.
Biomed Khim ; 65(5): 403-406, 2019 Aug.
Artigo em Russo | MEDLINE | ID: mdl-31666413

RESUMO

An imidazole derivative cramizol, has lipid-lowering and anti-atherogenic effects. Cramizol reduces blood levels of cholesterol and triglycerides, and also reduces the atherogenic index in animals with acute hyperlipidemia induced by Triton WR-1339. Cramizol and the lipid-lowering drug fenofibrate exhibited similar effectiveness as hypolipidemic agents. Cramizol also restores the expression of the Apoa1 gene in rats with experimentally induced hyperlipidemia to normal values. This may be a basis of its hypolipidemic and anti-atherogenic action.


Assuntos
Apolipoproteína A-I/genética , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/farmacologia , Imidazóis/farmacologia , Animais , Colesterol/sangue , Fenofibrato , Hiperlipidemias/genética , Ratos , Triglicerídeos/sangue
3.
J Vasc Res ; 56(5): 241-254, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31536996

RESUMO

PURPOSE: Atherosclerosis in the carotid arteries is a common cause of ischemic stroke. We examined atherogenesis in the left carotid artery with and without interrupted blood flow of C57BL/6 (B6) and C3H-Apoe-deficient (Apoe-/-) mouse strains. METHODS: Blood flow was interrupted by ligating the common carotid artery near its bifurcation in one group of mice and another group was not interrupted. RESULTS: Without interference with blood flow, C3H-Apoe-/- mice developed no atherosclerosis in the carotid artery, while B6-Apoe-/- mice formed advanced atherosclerotic lesions (98,019 ± 10,594 µm2/section) after 12 weeks of a Western diet. When blood flow was interrupted by ligating the common carotid artery near its bifurcation, C3H-Apoe-/- mice showed fatty streak lesions 2 weeks after ligation, and by 4 weeks fibrous lesions had formed, although they were smaller than in B6-Apoe-/- mice. Neutrophil adhesion to endothelium and infiltration in lesions was observed in ligated arteries of both strains. Treatment of B6-Apoe-/- mice with antibody against neutrophils had little effect on lesion size. CONCLUSIONS: These findings demonstrate the dramatic influences of genetic backgrounds and blood flow on atherogenesis in the carotid artery of hyperlipidemic mice.


Assuntos
Doenças das Artérias Carótidas/etiologia , Artéria Carótida Primitiva/fisiopatologia , Hiperlipidemias/complicações , Placa Aterosclerótica , Animais , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/patologia , Doenças das Artérias Carótidas/fisiopatologia , Artéria Carótida Primitiva/patologia , Artéria Carótida Primitiva/cirurgia , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Hiperlipidemias/genética , Ligadura , Masculino , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Fluxo Sanguíneo Regional , Especificidade da Espécie , Fatores de Tempo
4.
Curr Pharm Biotechnol ; 20(10): 825-844, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31264546

RESUMO

BACKGROUND: Cardiovascular Diseases (CVD) are, currently, the major contributor to global mortality and will continue to dominate mortality rates in the future. Hyperlipidemia refers to the elevated levels of lipids and cholesterol in the blood, and is also identified as dyslipidemia, manifesting in the form of different disorders of lipoprotein metabolism. These abnormalities may lead to the development of atherosclerosis, which can lead to coronary artery disease and stroke. In recent years, there is a growing interest in the quest for alternative therapeutic treatments based on natural products, offering better recovery and the avoidance of side effects. Recent technological advances have further improved our understanding of the role of epigenetic mechanisms in hyperlipidemic disorders and dietary prevention strategies. OBJECTIVE: This is a comprehensive overview of the anti-hyperlipidemic effects of plant extracts, vegetables, fruits and isolated compounds thereof, with a focus on natural products from the Mediterranean region as well as the possible epigenetic changes in gene expression or cardiometabolic signaling pathways. METHODS: For the purpose of this study, we searched the PubMed, Scopus and Google Scholar databases for eligible articles and publications over the last five years. The keywords included: "hyperlipidemia", "plant extract", "herbs", "natural products", "vegetables", "cholesterol" and others. We initially included all relevant articles referring to in vitro studies, animal studies, Randomized Controlled Trials (RCTs) and previous reviews. CONCLUSION: Many natural products found in the Mediterranean diet have been studied for the treatment of hyperlipidemia. The antihyperlipidemic effect seems to be dose and/or consumption frequency related, which highlights the fact that a healthy diet can only be effective in reversing disease markers if it is consistent and within the framework of a healthy lifestyle. Finally, epigenetic biomarkers are increasingly recognized as new lifestyle management tools to monitor a healthy dietary lifestyle for the prevention of hyperlipidaemic disorders and comorbidities to promote a healthy life.


Assuntos
Produtos Biológicos/farmacologia , Doenças Cardiovasculares/prevenção & controle , Dieta Mediterrânea , Epigênese Genética , Hiperlipidemias/prevenção & controle , Produtos Biológicos/isolamento & purificação , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Colesterol/sangue , Frutas/química , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/genética , Estilo de Vida , Verduras/química
5.
Clin Lab ; 65(7)2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31307169

RESUMO

BACKGROUND: The current study aims to explore the changes of serum miR-587 level in patients with metabolic syndrome (MS) and analyze its clinical diagnostic value. METHODS: The serum levels of miR-587 in 50 patients with hyperglycemia, 50 patients with hyperlipidemia, and 50 healthy controls were detected by RT-qPCR. The diagnostic value of serum miR-587 was detected by ROC analy-sis and correlation analysis in MS. Dual luciferase reporter assay was carried out to determine the possible target gene of miR-587. RESULTS: The results of RT-qPCR showed that the relative content of serum miR-587 in patients with hyperglyce-mia and hyperlipidemia was 0.45 ± 0.30, 0.41 ± 0.30, compared with 1 ± 0.87 in healthy people. The area under ROC curve (AUC) of serum miR-587 in hyperglycemic patients was 0.830 (95% CI = 0.716 - 0.863, p < 0.001), with the sensitivity of 68.6% and specificity of 89.3%. The AUC of serum miR-587 in hyperlipidemia patients was 0.790 (95% CI = 0.759 - 0.851, p < 0.001), with the sensitivity of 78% and specificity of 89.7%. Correlation analysis showed that serum miR-587 level was negatively correlated with fasting blood glucose (FBG) (r = -0.291, p < 0.05), and negatively correlated with total cholesterol (TC) (r = -0.243, p < 0.01). Furthermore, dual luciferase reporter assay showed that PTEN was the target gene of miR-587. CONCLUSIONS: In summary the decreased expression of miR-587 in serum is a potential diagnostic marker and in-dependent risk factor in patients with MS.


Assuntos
Biomarcadores/sangue , Regulação da Expressão Gênica , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , MicroRNAs/sangue , Glicemia/metabolismo , Colesterol/sangue , Jejum/sangue , Feminino , Humanos , Hiperglicemia/sangue , Hiperglicemia/diagnóstico , Hiperglicemia/genética , Hiperlipidemias/sangue , Hiperlipidemias/diagnóstico , Hiperlipidemias/genética , Masculino , Síndrome Metabólica/genética , MicroRNAs/genética , Pessoa de Meia-Idade , Curva ROC
6.
J Agric Food Chem ; 67(26): 7325-7335, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31184120

RESUMO

Tea polyphenols (TP) possess the ability to regulate dyslipidemia and gut microbiota dysbiosis. However, the underlying mechanism is still elusive. The present study explored the intervention of TP on high fat diet induced metabolic disorders, gut microbiota dysbiosis in mice, and the underlying intestinal mechanism. As a result, TP significantly ameliorated hyperlipidemia, improved the expression levels of hepatic lipid metabolism genes, and modulated gut microbiota. The underlying mechanism was supposed to rely on the maintaining of intestinal redox state by TP. Intestinal redox related indicators were significantly correlated with the distribution of gut microbiota. An unidentified genus of Lachnospiraceae, Bacteroides, Alistipes, and Faecalibaculum were identified as the biomarkers for intestinal redox state. Importantly, different dosages of TP modulated intestinal redox state and gut microbiota in varied patterns, and an overdose intake attenuated the beneficial effects on gut health. Our findings offered novel insights into the mechanism of TP on intestinal homeostasis.


Assuntos
Camellia sinensis/química , Microbioma Gastrointestinal/efeitos dos fármacos , Hiperlipidemias/tratamento farmacológico , Intestinos/microbiologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Polifenóis/administração & dosagem , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Dieta Hiperlipídica/efeitos adversos , Feminino , Humanos , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Hiperlipidemias/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Chá
7.
Clin Lab ; 65(6)2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31232032

RESUMO

BACKGROUND: The current study mainly evaluated whether peripheral blood miR-937 could be a biomarker to differentiate patients with metabolic disorders and healthy controls. METHODS: The peripheral blood was collected with patients with hyperglycemia, hyperlipidemia and healthy control. The relative peripheral blood miR-937 level in patients with metabolic disorders and healthy individuals were evaluated by real-time PCR. Receiver operating characteristic curve (ROC) analysis and Spearman's correlation coefficient were applied to evaluate whether miR-937 could be a potential biomarker for metabolic disorders. Dual luciferase reporter assay was performed to identify the possible target genes of miR-937. RESULTS: First, miR-937 was significantly increased (8.02 ± 8.27) in the peripheral blood of hyperglycemia patients. The level of miR-937 of patients with hyperlipidemia (13.7 ± 14.72) was also enhanced obviously compared with healthy controls (1 ± 1.35). ROC analysis showed that the peripheral blood levels of miR-937 could screen patients with hyperglycemia or hyperlipidemia from healthy controls. Furthermore, peripheral blood miR-937 level posi-tively correlated with serum glucose level (r = 0.556, p < 0.01) as well as total serum TG/TC levels (r = 0.455, p < 0.01). Dual luciferase reporter assay indicated that miR-937 suppressed the relative luciferase activity of pmir-GLO-AMPKα-3'UTR. CONCLUSIONS: The upregulation of circulating miR-937 level may cause a metabolism disorder by suppressing the expression of AMPKα. miR-937 could be a potential biomarker to differentiate patients with metabolism syndrome from healthy controls.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Biomarcadores/metabolismo , Doenças Metabólicas/genética , MicroRNAs/genética , Regiões 3' não Traduzidas/genética , Biomarcadores/sangue , Feminino , Regulação da Expressão Gênica , Células HEK293 , Células Hep G2 , Humanos , Hiperglicemia/sangue , Hiperglicemia/diagnóstico , Hiperglicemia/genética , Hiperlipidemias/sangue , Hiperlipidemias/diagnóstico , Hiperlipidemias/genética , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/diagnóstico , MicroRNAs/sangue , Pessoa de Meia-Idade , Curva ROC
8.
Eur J Clin Pharmacol ; 75(9): 1227-1235, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31172248

RESUMO

PURPOSE: Poor adherence to dietary/behaviour modifications as interventions for hypercholesterolemia in paediatric patients often necessitates the initiation of statin therapy. The aim of this study was to develop a joint population pharmacokinetic model for simvastatin and four metabolites in children and adolescents to investigate sources of variability in simvastatin acid exposure in this patient population, in addition to SLCO1B1 genotype status. METHODS: Plasma concentrations of simvastatin and its four metabolites, demographic and polymorphism data for OATP1B1 and CYP3A5 were analysed utilising a population pharmacokinetic modelling approach from an existing single oral dose (10 mg < 17 years and 20 mg ≥ 18 years) pharmacokinetic dataset of 32 children and adolescents. RESULTS: The population PK model included a one compartment disposition model for simvastatin with irregular oral absorption described by two parallel absorption processes each consisting of sequential zero and first-order processes. The data for each metabolite were described by a one-compartment disposition model with the formation and elimination apparent parameters estimated. The model confirmed the statistically significant effect of c.521T>C (rs4149056) on the pharmacokinetics of the active metabolite simvastatin acid in children/adolescents, consistent with adult data. In addition, age was identified as a covariate affecting elimination clearances of 6-hydroxymethyl simvastatin acid and 3, 5 dihydrodiol simvastatin metabolites. CONCLUSION: The model developed describes the pharmacokinetics of simvastatin and its metabolites in children/adolescents capturing the effects of both c.521T>C and age on variability in exposure in this patient population. This joint simvastatin metabolite model is envisaged to facilitate optimisation of simvastatin dosing in children/adolescents.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Modelos Biológicos , Sinvastatina/farmacocinética , Adolescente , Adulto , Criança , Citocromo P-450 CYP3A/genética , Feminino , Genótipo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Masculino , Sinvastatina/sangue , Adulto Jovem
9.
BMC Bioinformatics ; 20(Suppl 7): 201, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31074378

RESUMO

BACKGROUND: A key problem in systems biology is the determination of the regulatory mechanism corresponding to a phenotype. An empirical approach in this regard is to compare the expression profiles of cells under two conditions or tissues from two phenotypes and to unravel the underlying transcriptional regulation. We have proposed the method BASE to statistically infer the effective regulatory factors that are responsible for the gene expression differentiation with the help from the binding data between factors and genes. Usually the protein-DNA binding data are obtained by ChIP-seq experiments, which could be costly and are condition-specific. RESULTS: Here we report a definition of binding strength based on a probability model. Using this condition-free definition, the BASE method needs only the frequencies of cis-motifs in regulatory regions, thereby the inferences can be carried out in silico. The directional regulation can be inferred by considering down- and up-regulation separately. We showed the effectiveness of the approach by one case study. In the study of the effects of polyunsaturated fatty acids (PUFA), namely, docosahexaenoic (DHA) and eicosapentaenoic (EPA) diets on mouse small intestine cells, the inferences of regulations are consistent with those reported in the literature, including PPARα and NFκB, respectively corresponding to enhanced adipogenesis and reduced inflammation. Moreover, we discovered enhanced RORA regulation of circadian rhythm, and reduced ETS1 regulation of angiogenesis. CONCLUSIONS: With the probabilistic definition of cis-trans binding affinity, the BASE method could obtain the significances of TF regulation changes corresponding to a gene expression differentiation profile between treatment and control samples. The landscape of the inferred cis-trans regulations is helpful for revealing the underlying molecular mechanisms. Particularly we reported a more comprehensive regulation induced by EPA&DHA diet.


Assuntos
Indutores da Angiogênese/administração & dosagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Regulação da Expressão Gênica , Hiperlipidemias/genética , Motivos de Nucleotídeos , Transcrição Genética , Adipogenia/efeitos dos fármacos , Animais , Hiperlipidemias/tratamento farmacológico , Intestino Delgado/metabolismo , Camundongos , Regiões Promotoras Genéticas
10.
Genet Epidemiol ; 43(6): 617-628, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31087446

RESUMO

Lipid levels in blood are widely used to diagnose and monitor chronic diseases. It is essential to identify the genetic traits involved in lipid metabolism for understanding chronic diseases. However, the influence of genetic traits varies depending on race, sex, age, and ethnicity. Therefore, research focusing on populations of individual countries is required, and the results can be used as a basis for comparison of results of other studies at the cross-racial and cross-country levels. In the present study, we selected lipid-related variants and evaluated their effects on lipid-related diseases in more than 14,000 subjects of three cohorts using the Illumina Human Exome Beadchip. A genome-wide association study was conducted using EPACTs after adjusting for age, sex, and recruitment area. A genome-wide significance cutoff was defined as p < 5E-08 in all the three cohorts. Sixteen variants represented the lipid traits and were classified as vulnerable to borderline hypertriglyceridemia, hyper-LDL-cholesterolemia, or hypo-HDL-cholesterolemia. Moreover, we compared the genetic effects of the 16 variants between ethnic groups and identified the missense variants in apolipoprotein A-V, cholesterol ester transfer protein, and apolipoprotein E as Asian-specific. Our study provides candidate genes as markers for chronic diseases through the evaluation of genetic effects.


Assuntos
Grupos Étnicos/genética , Exoma , Estudo de Associação Genômica Ampla , Hiperlipidemias/etnologia , Hiperlipidemias/genética , Lipídeos/análise , Polimorfismo de Nucleotídeo Único , Grupo com Ancestrais do Continente Asiático/genética , Grupos Étnicos/classificação , Grupos Étnicos/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , República da Coreia
11.
Int J Biol Macromol ; 134: 759-769, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31100394

RESUMO

Reverse cholesterol transport (RCT) has been demonstrated to reduce hyperlipidemia, and fucoidans are found to possess hypolipidemic effect. This study was designed to investigate the lipid-lowering effect of the fucoidan from the brown seaweed A. nodosum and whether it improves RCT-related genes expression in C57 BL/6J mice. Our results indicated that fucoidan A3 (100 mg/kg/day) intervention significantly reduced plasma total cholesterol (~23.2%), triglyceride (~48.7%) and fat pad index. This fucoidan significantly increased the mRNA expression of low-density lipoprotein receptor (LDLR), scavenger receptor B type 1 (SR-B1), cholesterol 7 alpha-hydroxylase A1 (CYP7A1), liver X receptor (LXR) ß, ATP-binding cassette transporter (ABC) A1 and sterol regulatory element-binding protein (SREBP) 1c, and decreased the expression of peroxisome proliferator-activated receptor (PPAR) γ, however, it had no effect on the expression of proprotein convertase subtilisin/kexin type 9, PPARα, LXRα, SREBP-2, ABCG1, ABCG8 and Niemann-Pick C1-like 1. These results demonstrated that this fucoidan improved lipid transfer from plasma to the liver by activating SR-B1 and LDLR, and up-regulated lipid metabolism by activating LXRß, ABCA1 and CYP7A1. In conclusion, this fucoidan lowers lipid by enhancing RCT-related genes expression, and it can be explored as a potential candidate for prevention or treatment of lipid disorders.


Assuntos
Ascophyllum/química , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperlipidemias/genética , Polissacarídeos/farmacologia , Alga Marinha/química , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Transporte Biológico , Colesterol/metabolismo , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Modelos Animais de Doenças , Hiperlipidemias/metabolismo , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Intestino Delgado/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Polissacarídeos/química , RNA Mensageiro , Receptores de LDL/genética , Receptores de LDL/metabolismo , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo
12.
Mol Pharmacol ; 96(1): 47-55, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064810

RESUMO

Westernization of dietary habits increases lipid intake and is responsible for increased numbers of patients with atherosclerotic diseases. Niemann-Pick C1-Like 1 (NPC1L1)-a cholesterol importer-plays a crucial role in dietary cholesterol absorption in the intestine and is closely associated with several lipid-related diseases, including atherosclerosis. NPC1L1 is highly expressed in the liver and intestine in humans, whereas NPC1L1 expression is low in the rodent liver. Due to species differences in the tissue distribution of NPC1L1, there are limited studies on the pathophysiological role of hepatic NPC1L1, a cholesterol reabsorber from bile. In the present study, to explore whether hepatic NPC1L1 is involved in the development/progression of atherosclerosis, we compared four kinds of atherosclerosis mouse models with different expression levels of NPC1L1 in the intestinal and liver tissues in a genetic background of dysfunctional low-density lipoprotein receptor mutation. Western diet (WD)-induced hyperlipidemia and atherosclerotic plaque formation were more severe in mice expressing NPC1L1 in both the liver and intestine (plasma cholesterol, 839.5 mg/dl; plaque area, 29.5% of total aorta), compared with mice expressing NPC1L1 only in the intestine (plasma cholesterol, 573.1 mg/dl; plaque area, 13.3% of total aorta). Such hepatic NPC1L1-mediated promotion of hyperlipidemia and atherosclerosis was not observed in mice not expressing intestinal NPC1L1 and mice treated with ezetimibe, an NPC1L1 inhibitor used clinically for dyslipidemia. These results suggested that hepatic NPC1L1 promotes WD-induced dyslipidemia and atherosclerosis in concert with intestinal NPC1L1. Our findings provide novel insights into the pathophysiological importance of hepatic NPC1L1 in development/progression of atherosclerosis. SIGNIFICANCE STATEMENT: Niemann-Pick C1-Like 1 (NPC1L1) protein, a cholesterol importer and a molecular target of ezetimibe clinically used for dyslipidemia, is highly expressed not only in the intestine, but also in the liver in humans, although the pathophysiological importance of hepatic NPC1L1 in atherosclerotic diseases remained unclear. By using novel mouse models to separately analyze the effects of hepatic and intestinal NPC1L1 on the development/progression of atherosclerosis, we first demonstrated that hepatic NPC1L1 accelerates Western diet-induced atherosclerotic plaque formation in an intestinal NPC1L1-dependent and an ezetimibe-sensitive manner.


Assuntos
Dieta Ocidental/efeitos adversos , Hiperlipidemias/metabolismo , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Receptores de LDL/genética , Animais , Aterosclerose/induzido quimicamente , Aterosclerose/genética , Aterosclerose/metabolismo , Colesterol/metabolismo , Modelos Animais de Doenças , Ezetimiba/farmacologia , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/genética , Masculino , Camundongos , Mutação , Receptores de LDL/metabolismo , Regulação para Cima
13.
J Agric Food Chem ; 67(20): 5782-5791, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31055921

RESUMO

Reverse cholesterol transport (RCT) is a physiological process, in which excess peripheral cholesterol is transported to the liver and further excreted into the bile and then feces. Recently, fucoidans are reported to have a lipid-lowering effect. This study was designed to investigate whether fucoidan from the brown seaweed Ascophyllum nodosum lowers lipid by modulating RCT in C57BL/6J mice fed a high-fat diet. Our results indicated that fucoidan intervention significantly reduced plasma triglyceride, total cholesterol, and fat pad index and markedly increased high-density lipoprotein cholesterol in a dose-dependent manner. In the liver, fucoidan significantly increased the expression of peroxisome proliferator-activated receptor (PPAR)α, PPARγ, liver X receptor (LXR)ß, adenosine triphosphate (ATP) binding cassette (ABC)A1, ABCG8, low-density lipoprotein receptor (LDLR), scavenger receptor B type 1 (SR-B1), and cholesterol 7-α-hydroxylase A1 (CYP7A1) and decreased the triglyceride level and expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) and PPARß but had no effect on LXRα, ABCG1, and ABCG5. In the small intestine, the fucoidan treatment significantly reduced the expression of Niemann-Pick C1-like 1 (NPC1L1) and improved ABCG5 and ABCG8. These results demonstrated that fucoidan can improve lipid transfer from plasma to the liver by activating SR-B1 and LDLR and inactivating PCSK9 and upregulate lipid metabolism by activating PPARα, LXRß, ABC transporters, and CYP7A1. In the small intestine, this fucoidan can decrease cholesterol absorption and increase cholesterol excretion by activating NPC1L1 and ABCG5 and ABCG8, respectively. In conclusion, fucoidan from A. nodosum may lower lipids by modulating RCT-related protein expression and can be explored as a potential compound for prevention or treatment of hyperlipidemia-related diseases.


Assuntos
Ascophyllum/química , Colesterol/metabolismo , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Metabolismo dos Lipídeos/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Polissacarídeos/administração & dosagem , Alga Marinha/química , 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 , Animais , Transporte Biológico/efeitos dos fármacos , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Dieta Hiperlipídica/efeitos adversos , Humanos , Hiperlipidemias/etiologia , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores de LDL/genética , Receptores de LDL/metabolismo , Receptores Depuradores/genética , Receptores Depuradores/metabolismo
14.
Food Funct ; 10(5): 2330-2339, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31049523

RESUMO

With great changes in people's lifestyles, the incidence of hyperlipidaemia has dramatically increased in recent years. Numerous studies have demonstrated that natural polysaccharides have lipid lowering effects. In this review, the causes and mechanisms of hyperlipidaemia are discussed in order to better understand how polysaccharides alleviate hyperlipidaemia. Natural polysaccharides reduce triglyceride levels through ATGL-(PPAR-α)/(PGC-1α), (SREBP-1c)-ACC/FAS and ACC-CPT1 signal pathways, and exert cholesterol lowering effects via (SREBP-2)-HMGCR and bile acid biosynthesis pathways. Activation of adenosine monophosphate-activated protein kinase (AMPK) is the key factor that mediated the simultaneous regulation of both glucose and lipid metabolism by polysaccharides. The new discovery of polysaccharides increasing the production of endogenous H2S, an important physiological gaseous signaling molecule, is also discussed. Collectively, the current available data suggest that natural polysaccharides could be potentially developed as new and safe lipid-lowering drugs; yet further mechanistic and clinical studies are required during this long-term process.


Assuntos
Colesterol/metabolismo , Hiperlipidemias/tratamento farmacológico , Polissacarídeos/administração & dosagem , Triglicerídeos/metabolismo , Animais , Humanos , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
15.
J Periodontal Res ; 54(5): 546-554, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31032950

RESUMO

BACKGROUND AND OBJECTIVE: CYP1A1 rs1048943 polymorphism was reported to be correlated with periodontitis; however, its association with aggressive periodontitis (AgP) has not yet been investigated. The aim of the study was to investigate the association between the CYP1A1 gene rs1048943 variant with generalized aggressive periodontitis (GAgP) and platelet activation and analyse whether its interaction with hyperlipidemia affects periodontal status in a Chinese population. METHODS: A case-control study of 224 GAgP patients and 139 healthy controls was conducted. The clinical parameters of probing depth (PD), attachment loss (AL) and bleeding index (BI) were recorded. Platelet count (PLT), platelet distribution width (PDW), platelet large cell ratio (PLCR), mean platelet volume (MPV), serum total cholesterol (TC), triacylglycerol (TG), high and low-density lipoprotein (HDL and LDL) were also measured. The CYP1A1 rs1048943 SNP was genotyped by time-of-flight mass spectrometry. Logistic and linear regression models were used to measure correlation. RESULTS: The CYP1A1 rs1048943 AG/GG genotype was associated with GAgP (OR = 1.56, 95%CI: 1.01, 2.42), PD, AL and decreased PDW, PLCR and MPV after adjustment for covariates. Gene-lipid interactions were found between CYP1A1 rs1048943 and HDL for PD (Pinteraction  = 0.0033), BI (Pinteraction  = 0.0311) and AL (Pinteraction  = 0.0141) and between CYP1A1 rs1048943 and LDL for PD (Pinteraction  = 0.013) among patients with GAgP. CONCLUSION: The G allele of the CYP1A1 rs1048943 gene was associated with GAgP, periodontal status and platelet-related inflammation status in a Chinese population. Hyperlipidemia could modulate the effect of CYP1A1 rs1048943 on the periodontal status of GAgP.


Assuntos
Periodontite Agressiva , Citocromo P-450 CYP1A1 , Hiperlipidemias , Periodontite Agressiva/genética , Alelos , Estudos de Casos e Controles , China , Citocromo P-450 CYP1A1/genética , Humanos , Hiperlipidemias/genética , Triglicerídeos
16.
J Agric Food Chem ; 67(16): 4524-4534, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30945544

RESUMO

Dietary polyphenols have shown hypolipidemic effects by reducing triglyceride absorption. The mechanisms may involve modifying fat emulsion during digestion in the gastrointestinal tract and suppressing lipase during hydrolysis in the small intestine. In an in vivo study, lotus seedpod oligomeric procyanidin (LSOPC) decreased total serum triglyceride and total cholesterol and elevated the high-density lipoprotein level in the hyperlipidemic rat model. In addition, LSOPC suppressed de novo lipogenesis-related gene expressions. In an in vitro study, the LSOPC-enriched emulsion decreased the mean droplet size from 0.36 to 0.33 µm and increased the viscosity of the emulsion. Moreover, the LSOPC-enriched emulsion improved the antioxidant properties. A digestion model was developed and showed that the particle size of the LSOPC-enriched emulsion increased in the oral cavity. However, an increase and then a significant drop of the particle size was measured in the stomach and small intestine. The free fatty acid release rate was decreased in the LSOPC-enriched emulsion partly ascribed to the inhibition of lipase by LSOPC.


Assuntos
Biflavonoides/metabolismo , Catequina/metabolismo , Gorduras/metabolismo , Hiperlipidemias/dietoterapia , Metabolismo dos Lipídeos , Lotus/metabolismo , Extratos Vegetais/metabolismo , Proantocianidinas/metabolismo , Animais , Biflavonoides/química , Catequina/química , Digestão , Emulsões/química , Emulsões/metabolismo , Gorduras/química , Mucosa Gástrica/metabolismo , Homeostase , Humanos , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Hiperlipidemias/fisiopatologia , Mucosa Intestinal/metabolismo , Intestinos , Lotus/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Tamanho da Partícula , Extratos Vegetais/química , Proantocianidinas/química , Ratos , Ratos Sprague-Dawley , Sementes/química , Sementes/metabolismo
17.
Life Sci ; 227: 201-211, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31002917

RESUMO

AIMS: Colorectal cancer syndrome has been one of the greatest concerns in the world. Although several epidemiological studies have shown that hepatic low lipoprotein lipase (LPL) mRNA expression may be associated with dyslipidemia and tumor progression, it is still not known whether the liver plays an essential role in hyperlipidemia of ApcMin/+ mice. MAIN METHODS: We measured the expression of metabolic enzymes that involved fatty acid uptake, de novo lipogenesis (DNL), ß-oxidation and investigated hepatic triglyceride production in the liver of wild-type and ApcMin/+ mice. KEY FINDINGS: We found that hepatic fatty acid uptake and DNL decreased, but there was no significant difference in fatty acid ß-oxidation. Interestingly, the production of hepatic very low-density lipoprotein-triglyceride (VLDL-TG) decreased at 20 weeks of age, but marked steatosis was observed in the livers of the ApcMin/+ mouse. To further explore hypertriglyceridemia, we assessed the function of hepatic glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) for the first time. GPIHBP1 is governed by the transcription factor octamer-binding transcription factor-1 (Oct-1) which are involved in the nuclear factor-κB (NF-κB) signaling pathway in the liver of ApcMin/+ mice. Importantly, it was also confirmed that sn50 (100 µg/mL, an inhibitor of the NF-κB) reversed the tumor necrosis factor α (TNFα)-induced Oct-1 and GPIHBP1 reduction in HepG2 cells. SIGNIFICANCE: Altogether, these findings highlighted a novel role of GPIHBP1 that might be responsible for hypertriglyceridemia in ApcMin/+ mice. Hypertriglyceridemia in these mice may be associated with their hepatic lipid metabolism development.


Assuntos
Fígado/metabolismo , Receptores de Lipoproteínas/fisiologia , Triglicerídeos/metabolismo , Animais , Caquexia/metabolismo , Caquexia/fisiopatologia , Neoplasias do Colo/fisiopatologia , Ácidos Graxos/metabolismo , Fígado Gorduroso/patologia , Regulação da Expressão Gênica/genética , Células Hep G2 , Humanos , Hiperlipidemias/genética , Metabolismo dos Lipídeos/genética , Lipídeos/fisiologia , Lipogênese/fisiologia , Lipólise/fisiologia , Lipoproteínas VLDL/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 1 de Transcrição de Octâmero/fisiologia , Receptores de Lipoproteínas/genética , Receptores de Lipoproteínas/metabolismo , Triglicerídeos/genética , Fator de Necrose Tumoral alfa/fisiologia
18.
Lipids Health Dis ; 18(1): 104, 2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31010436

RESUMO

BACKGROUND: In recent years, an increasing number of studies have proved that circulating miRNAs could be used for the early diagnosis of cardiovascular diseases and even play vital roles in the evaluation of therapeutic effects or prognosis. This study was conducted to examine the correlation between serum microRNAs and hyperlipidemia to provide a theoretical basis for the early screening and intervention of atherosclerotic cardiovascular diseases (ASCVD). METHODS: The serum samples and clinical data of 122 patients with hyperlipidemia and 168 healthy subjects were collected. Related clinical information was statistically analyzed for the two groups. Expression of circulating miRNAs was detected by miRNA microarray analysis and further verified by reverse transcription-quantitative PCR (RT-qPCR). RESULTS: Statistical analysis of clinical information revealed a significant difference in the incidence of ASCVD between the two groups. The MiRNA microarray analysis (n = 10) showed 22 miRNAs with significantly different expression, among which 12 showed upregulation, and the others showed downregulation. Those possessing obvious differences and stable expression in the miRNA microarray, including miRNA-191-3p, miRNA-933, and miRNA-425-3p, were chosen for further investigation using RT-qPCR. The results demonstrated that several miRNAs were related to lipid metabolism disorders, especially miRNA-933. The area under the curve (AUC) of miRNA-933 in distinguishing the hyperlipidemia and ASCVD patients was 0.739 (95% CI, 0.682-0.795; P < 0.01) and 0.703 (95% CI, 0.643-0.763, P < 0.01), respectively. CONCLUSIONS: In conclusion, miRNA-191-3p, miRNA-933, and miRNA-425-3p may be depressed in the peripheral circulation of patients with lipid metabolism disorders (mainly LDL). Circulating miRNA-933 could be a feasible predictor for ASCVD at the early stage.


Assuntos
Aterosclerose/sangue , Aterosclerose/genética , MicroRNA Circulante/genética , Hiperlipidemias/sangue , Hiperlipidemias/genética , Área Sob a Curva , Estudos de Casos e Controles , MicroRNA Circulante/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade
19.
Genes (Basel) ; 10(3)2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934611

RESUMO

The effects of genetic variants on the interaction between hyperlipidemia and sex have not been investigated among gout patients in Taiwan. Using Taiwan Biobank and the National Health Insurance Research Database (NHIRD), we examined hyperlipidemia, sex, and their relationship with gout among Taiwanese adults with the human leukocyte antigen B (HLA-B) genetic variants. Hyperlipidemia was present in 1437 patients with gout. Sex and hyperlipidemia had significant associations on gout risk, with hyperlipidemia showing a relatively stronger effect. Gout was present in men, with an odds ratio (OR) of 1.945 (95% confidence interval (CI) 1.568⁻2.411) compared to women, and in hyperlipidemic (OR = 4.032; 95% CI: 3.581⁻4.540) compared to non-hyperlipidemic patients. The interaction of sex and hyperlipidemia was significant for rs2523608 GG (p = 0.0402) and rs4713518 AA (p = 0.0003) genotypes. After stratification, hyperlipidemia remained a risk factor in women (OR = 4.735, 95% CI: 3.375⁻6.643) and men (OR = 3.640, 95% CI: 2.916⁻4.544) with rs2523608 GG genotype. The odds ratio in hyperlipidemic women and men with rs4713518 AA genotype was 7.454 (95% CI 5.103⁻10.888) and 3.585 (95% CI 2.854⁻4.503), respectively. Our study indicates that hyperlipidemia-sex interactions exist for gout risk in Taiwanese adults with rs2523608 GG and rs4713518 AA genotypes.


Assuntos
Gota/genética , Antígenos HLA-B/genética , Hiperlipidemias/epidemiologia , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Humanos , Hiperlipidemias/genética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Caracteres Sexuais , Taiwan/epidemiologia
20.
Arterioscler Thromb Vasc Biol ; 39(6): 1055-1071, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30943771

RESUMO

Objective- Vascular adventitia encompasses progenitors and is getting recognized as the major site of inflammation in early stage of atherosclerosis. However, the cellular atlas of the heterogeneous adventitial cells, the intercellular communication, the cellular response of adventitia to hyperlipidemia, and its contribution to atherosclerosis have been elusive. Approach and Results- Single-cell RNA sequencing was applied to wt (wild type) and ApoE (apolipoprotein E)-deficient aortic adventitia from 12-week-old C57BL/6J mice fed on normal laboratory diet with early stage of atherosclerosis. Unbiased clustering analysis revealed that the landscape of adventitial cells encompassed adventitial mesenchyme cells, immune cells (macrophages, T cells, and B cells), and some types of rare cells, for example, neuron, lymphatic endothelial cells, and innate lymphoid cells. Seurat clustering analysis singled out 6 nonimmune clusters with distinct transcriptomic profiles, in which there predominantly were stem/progenitor cell-like and proinflammatory population (Mesen II). In ApoE-deficient adventitia, resident macrophages were activated and related to increased myeloid cell infiltration in the adventitia. Cell communication analysis further elucidated enhanced interaction between a mesenchyme cluster and inflammatory macrophages in ApoE-deficient adventitia. In vitro transwell assay confirmed the proinflammatory role of SCA1+ (stem cell antigen 1 positive) Mesen II population with increased CCL2 (chemokine [C-C motif] ligand 2) secretion and thus increased capacity to attract immune cells in ApoE-deficient adventitia. Conclusions- Cell atlas defined by single-cell RNA sequencing depicted the heterogeneous cellular landscape of the adventitia and uncovered several types of cell populations. Furthermore, resident cell interaction with immune cells appears crucial at the early stage of atherosclerosis.


Assuntos
Túnica Adventícia/metabolismo , Apolipoproteínas E/genética , Aterosclerose/genética , Células Endoteliais/metabolismo , Hiperlipidemias/genética , Túnica Adventícia/citologia , Animais , Aterosclerose/fisiopatologia , Células Cultivadas , Análise por Conglomerados , Modelos Animais de Doenças , Células Endoteliais/citologia , Linfócitos/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pericitos/metabolismo , Distribuição Aleatória , Valores de Referência , Análise de Sequência de RNA/métodos
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