RESUMO
PURPOSE: The sun mushroom (Agaricus brasiliensis) is considered a major source of bioactive compounds with potential health benefits. Mushrooms typically act as lipid-lowering agents; however, little is known about the mechanisms of action of A. brasiliensis in biological systems. This study aimed to determine the underlying mechanism involved in the cholesterol-lowering effect of A. brasiliensis through the assessment of fecal and serum lipid profiles in addition to gene expression analysis of specific transcription factors, enzymes, and transporters involved in cholesterol homeostasis. METHODS: Twenty-four albino Fischer rats approximately 90 days old, with an average weight of 205 g, were divided into four groups of 6 each and fed a standard AIN-93 M diet (C), hypercholesterolemic diet (H), hypercholesterolemic diet +1 % A. brasiliensis (HAb), or hypercholesterolemic diet +0.008 % simvastatin (HS) for 6 weeks. Simvastatin was used as a positive control, as it is a typical drug prescribed for lipid disorders. Subsequently, blood, liver, and feces samples were collected for lipid profile and quantitative real-time polymerase chain reaction gene expression analyses. RESULTS: Diet supplementation with A. brasiliensis significantly improved serum lipid profiles, comparable to the effect observed for simvastatin. In addition, A. brasiliensis dietary supplementation markedly promoted fecal cholesterol excretion. Increased expression of 7α-hydroxylase (CYP7A1), ATP-binding cassette subfamily G-transporters (ABCG5/G8), and low-density lipoprotein receptor (LDLR) was observed following A. brasiliensis administration. CONCLUSIONS: Our results suggest that consumption of A. brasiliensis improves the serum lipid profile in hypercholesterolemic rats by modulating the expression of key genes involved in hepatic cholesterol metabolism.
Assuntos
Agaricales/química , Agaricus/química , Colesterol/sangue , Homeostase/genética , Hipercolesterolemia/sangue , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 5 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/sangue , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Colesterol 7-alfa-Hidroxilase/sangue , Colesterol 7-alfa-Hidroxilase/genética , Colesterol na Dieta/administração & dosagem , Colesterol na Dieta/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Metabolismo dos Lipídeos/genética , Lipoproteínas/sangue , Lipoproteínas/genética , Lipoproteínas/metabolismo , Ratos , Ratos Endogâmicos F344 , Receptores de LDL/sangue , Receptores de LDL/genéticaAssuntos
Membro 5 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/genética , Transtornos Plaquetários/genética , Hipercolesterolemia/genética , Enteropatias/genética , Erros Inatos do Metabolismo Lipídico/genética , Lipoproteínas/genética , Fitosteróis/efeitos adversos , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Animais , Transtornos Plaquetários/sangue , Feminino , Humanos , Lipoproteínas/sangue , Masculino , Camundongos , Fitosteróis/genéticaAssuntos
Apolipoproteína B-100/genética , Hiperlipoproteinemia Tipo II/genética , Mutação , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 5 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/sangue , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Proteínas Adaptadoras de Transdução de Sinal/sangue , Proteínas Adaptadoras de Transdução de Sinal/genética , Apolipoproteína B-100/sangue , Apolipoproteínas E/sangue , Apolipoproteínas E/genética , LDL-Colesterol/sangue , Bases de Dados Genéticas , Expressão Gênica , Genômica/métodos , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/patologia , Metabolismo dos Lipídeos/genética , Lipoproteínas/sangue , Lipoproteínas/genética , Pró-Proteína Convertase 9/sangue , Receptores de LDL/sangue , Esterol Esterase/sangue , Esterol Esterase/genéticaRESUMO
BACKGROUND: Sitosterolemia is a rare inherited lipid metabolic disorder characterized by increased levels of plant sterols and accelerated atherosclerosis. Although early detection is beneficial for the prevention of disease progression, it is largely underdiagnosed by routine screening based on conventional lipid profiles. MATERIALS AND METHODS: A gas chromatography-mass spectrometry (GC-MS)-based profiling has been developed and validated to measure the levels of biologically active free sterols, including five endogenous sterols and three plant sterols (sitosterol, campesterol, and stigmasterol) in dried blood spot (DBS). RESULTS: Within- and between-run precisions were 1.4-11.1 % and 2.2-14.1 %, respectively, while the accuracies were all 86.3 â¼ 121.9 % with the correlation coefficients (r2) > 0.988 for all the sterols. In the patients (four girls and two boys, 6.5 ± 2.8 years), sitosterol levels were significantly increased, with an optimal cut-off value of 2.5 µg/mL distinguishing them from ninety-three age-matched healthy children. A cut-off value of 31.9 µg/mL differentiated the patients from six ABCG5/ABCG8 heterozygous carriers. In addition, the molecular ratios of sitosterol to cholesterol, desmosterol, and 7-dehydrocholesterol provided excellent cut-off values of 26.3, 67.6, and 21.6, respectively, to distinguish patients from both healthy controls and heterozygous carriers. CONCLUSIONS: The novel DBS-based GC-MS profiling of free sterols accurately identified patients with sitosterolemia, with a performance comparable to that of a serum assay. The DBS profiling could be more feasible method in clinical practice as well as population screening programs, and it can provide diagnostic cut-off values for individual plant sterols.
Assuntos
Teste em Amostras de Sangue Seco , Cromatografia Gasosa-Espectrometria de Massas , Hipercolesterolemia , Enteropatias , Erros Inatos do Metabolismo Lipídico , Fitosteróis , Humanos , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/diagnóstico , Feminino , Masculino , Enteropatias/sangue , Enteropatias/diagnóstico , Criança , Fitosteróis/sangue , Fitosteróis/efeitos adversos , Teste em Amostras de Sangue Seco/métodos , Hipercolesterolemia/sangue , Hipercolesterolemia/diagnóstico , Pré-Escolar , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Esteróis/sangue , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Lipoproteínas/sangueRESUMO
Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD.
Assuntos
Colesterol/sangue , Doença da Artéria Coronariana/genética , Loci Gênicos , Metabolismo dos Lipídeos/genética , Fitosteróis/sangue , Sistema ABO de Grupos Sanguíneos/sangue , Sistema ABO de Grupos Sanguíneos/genética , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 5 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/sangue , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Apolipoproteínas E/sangue , Apolipoproteínas E/genética , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/patologia , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Hidroximetilglutaril-CoA Redutases/sangue , Hidroximetilglutaril-CoA Redutases/genética , Lipase/sangue , Lipase/genética , Lipoproteínas/sangue , Lipoproteínas/genética , Masculino , Proteínas de Membrana Transportadoras/sangue , Proteínas de Membrana Transportadoras/genética , Análise da Randomização Mendeliana , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Receptores Depuradores Classe B/sangue , Receptores Depuradores Classe B/genéticaRESUMO
Classical lipid transporters are suggested to modulate cellular vitamin D uptake. This study investigated the vitamin D levels in serum and tissues of mice deficient in SR-B1 (Srb1-/-), CD36 (Cd36-/-) and ABC-G5/G8 (Abcg5/g8-/-) and compared them with corresponding wild-type (WT) mice. All mice received triple-deuterated vitamin D3 (vitamin D3-d3) for six weeks. All knockout mice vs. WT mice showed specific alterations in their vitamin D concentrations. Srb1-/- mice had higher levels of vitamin D3-d3 in the serum, adipose tissue, kidney and heart, whereas liver levels of vitamin D3-d3 remained unaffected. Additionally, Srb1-/- mice had lower levels of deuterated 25-hydroxyvitamin D3 (25(OH)D3-d3) in the serum, liver and kidney compared to WT mice. In contrast, Cd36-/- and WT mice did not differ in the serum and tissue levels of vitamin D3-d3, but Cd36-/- vs. WT mice were characterized by lower levels of 25(OH)D3-d3 in the serum, liver and kidney. Finally, Abcg5/g8-/- mice tended to have higher levels of vitamin D3-d3 in the serum and liver. Major alterations in Abcg5/g8-/- mice were notably higher levels of 25(OH)D3-d3 in the serum and kidney, accompanied by a higher hepatic mRNA abundance of Cyp27a1 hydroxylase. To conclude, the current data emphasize the significant role of lipid transporters in the uptake, tissue distribution and activation of vitamin D.
Assuntos
Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Lipoproteínas/sangue , Receptores Depuradores Classe B/sangue , Receptores Depuradores Classe B/deficiência , Vitamina D/sangue , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/deficiência , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/deficiência , Animais , Transporte Biológico , Peso Corporal , Antígenos CD36/sangue , Antígenos CD36/deficiência , Calcifediol/sangue , Colesterol/sangue , Desidrocolesteróis/sangue , Feminino , Rim/metabolismo , Lipoproteínas/deficiência , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transaminases/sangue , Triglicerídeos/sangue , Vitamina D/farmacocinéticaRESUMO
Low-density lipoprotein cholesterol (LDL-C) plays a causal role in atherosclerosis. One way to reduce LDL-C levels is to inhibit cholesterol absorption. Plant sterols and stanols compete with cholesterol for absorption in the intestine and induce an average decrease in LDL-C by 5% to 15% in a dose-dependent manner, but not in all individuals. This review focuses on the interindividual variability in response to dietary supplementation with plant sterols and stanols. Dietary plant sterols and stanols have no significant effects on LDL-C in substantial numbers of individuals. Higher responses, in absolute value and percentage of LDL-C, are observed in individuals with higher cholesterol absorption and a lower rate of cholesterol synthesis. Some data provide evidence of the influence of genetics on the response to plant sterols and stanols. Further studies in large populations are required to extend these conclusions about genetic influences.