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Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2015-10-15T12:44:52Z No. of bitstreams: 2 Dissertação - Maira Chiquito Alves - 2015.pdf: 2795650 bytes, checksum: df30e15f25e56e8cea5234d554455c1b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2015-10-15T12:46:45Z (GMT) No. of bitstreams: 2 Dissertação - Maira Chiquito Alves - 2015.pdf: 2795650 bytes, checksum: df30e15f25e56e8cea5234d554455c1b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2015-10-15T12:46:45Z (GMT). No. of bitstreams: 2 Dissertação - Maira Chiquito Alves - 2015.pdf: 2795650 bytes, checksum: df30e15f25e56e8cea5234d554455c1b (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-03-20 / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / To verify the relationship between the polymorphisms rs18011282 in PPAR-gamma gene and rs429358 + rs7412 in apolipoprotein E gene and lipid profile of adolescents under cardiovascular risk factors. Material and methods: The study sample was composed of 115 adolescents aged 10-19 years, which presented cardiovascular risk factors. The students were evaluated regarding socioeconomic, anthropometric, biochemical, genetic and dietetic variables. ANOVA or Kruskal-Wallis tests were used in the analysis of ungrouped genotypes, while Student’s t-test or Mann-Whitney test were applied to the analysis of the grouped genotypes. Results: The overweight adolescents presented lower HDL-c concentrations (p=0.0016). Those carrying PPAR-gamma Ala allele showed higher serum TAG (p=0.0423) and VLDL-c (p=0.0410) levels when compared to those carrying the Pro allele. For the apolipoprotein E gene polymorphism, it was observed a tendency of higher TAG (p=0.0712) and VLDL-c (p=0.0758) levels in the adolescents carrying the E4 allele when compared to those who did not carry this allele. Conclusion: The polymorphisms PPAR-gama rs18011282 and apolipoprotein E rs429358 + rs7412 seem to be related to the development of lipid profile alterations in adolescents. / Verificar a relação dos polimorfismos rs18011282 no gene do PPAR-gama e rs429358 + rs7412 no gene da apolipoproteína E com o perfil lipídico de adolescentes com fatores de risco cardiovascular. Material e métodos: A amostra foi constituida por 115 adolescentes com idade entre 10-19 anos e com fatores de risco cardiovascular. Os estudantes foram avaliados quanto as variáveis socioeconômicas, antropométricas, bioquímicas, genéticas e dietéticas. Os testes ANOVA ou Kruskal-Wallis foram utilizados para os genótipos não agrupados, e as análises dos genótipos agrupados foram realizadas por meio dos testes t de Student e Mann-Whitney. Resultados: Os adolescentes com excesso de peso apresentaram concentrações inferiores de HDL-c (p=0,0016). Carreadores do alelo variante Ala (PPAR-gama) apresentaram concentrações séricas superiores de TG (p=0,0423) e de VLDL-c (p=0,0410) em relação ao carreadores do alelo selvagem Pro. Para o polimorfismo no gene da ApoE foram observadas concentrações séricas de TG (p=0,0712) e de VLDL-c (p=0,0758) marginalmente maiores nos carreadores do alelo E4 em relação aos não carreadores deste alelo. Conclusão: Os polimorfismos rs18011282 no gene que codifica o PPAR-gama e rs429358 + rs7412 no gene que codifica a ApoE podem estar relacionados ao desenvolvimento de dislipidemias em adolescentes.

Submitted by Franciele Moreira (francielemoreyra@gmail.com) on 2017-11-21T17:24:03Z No. of bitstreams: 2 Tese - Max Weyler Nery - 2013.pdf: 3823648 bytes, checksum: 45da627ca3fc33274b6ed62abbaf86f2 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2017-11-22T10:12:26Z (GMT) No. of bitstreams: 2 Tese - Max Weyler Nery - 2013.pdf: 3823648 bytes, checksum: 45da627ca3fc33274b6ed62abbaf86f2 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-11-22T10:12:26Z (GMT). No. of bitstreams: 2 Tese - Max Weyler Nery - 2013.pdf: 3823648 bytes, checksum: 45da627ca3fc33274b6ed62abbaf86f2 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2013-05-16 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / A highly active antiretroviral therapy (HAART) has significantly reduced the morbidity and mortality of HIV infection. The greatest survival, chronic inflammation and metabolic changes resulting from HAART are associated with increased cardiovascular disease (CVD). Objectives: To evaluate the correlation between CVD risk scores; estimate the frequency of evaluating the metabolic and obtaining lipid targets in HIV-positive patients. Method: Cohort of seropositive individuals recruited at a referral center for HIV, in Goiás, 2009-2011. 294 participants aged >19 years were followed with clinical and laboratory evaluations performed at baseline, after 3 and 6 months. We analyzed the correlation between Framingham with and without aggravating factors; PROCAM and DAD (Kappa). We estimated the frequency of metabolic changes and obtaining lipid targets, post-intervention, according to Guidelines of the Brazilian Society of Cardiology. According to clinical and laboratory criteria, patients received rosuvastina and/or ciprofibrate. The level of significance was set at p<5%. SPSS 18.0 software was used. Results: predominantly male population (76.9%); with a mean age of 36.8 years (SD=10.3); 66.3% on HAART, of whom 50.0% for less than two years. High risk of CVD ranged from 0.4 to 5.7%. Intermediate risk for CVD was seen in 3.2, according to the Framingham score and 39.9% of the participants, considering the presence of aggravating factors. At baseline, 72.8% of participants had some type of dyslipidemia. There was a significant reduction in the percentage of individuals with mixed dyslipidemia and low HDL, post-deployment lipid targets (p<0.05). Conclusions: Framingham with aggravating factors seems to overestimate cardiovascular risk in HIV positive patients. One third of patients with dyslipidemia reached lipid treatment targets in six months. Further studies are needed to assess the predictive power of different risk scores, as well as to assess the benefits of medium and long-term use of statins in this population. / A terapia antirretroviral (TARV) potente reduziu de forma significativa a morbidade e a mortalidade da infecção pelo HIV. A maior sobrevida, o processo inflamatório crônico e as alterações metabólicas decorrentes da TARV estão associados a um aumento de doenças cardiovasculares (DCV). Objetivos: Avaliar a concordância entre escores de risco para DCV; estimar a frequência de alterações metabólicas e avaliar a obtenção de metas lipídicas, em pacientes HIV positivos. Método: Coorte de indivíduos soropositivos recrutados em centro de referência para HIV, em Goiás, de 2009 a 2011. Foram acompanhados 294 participantes com idade > 19 anos, sendo realizadas avaliações clínicas e laboratoriais na admissão, após 3 e 6 meses. Analisou-se a concordância entre: Framingham, com e sem fatores agravantes; PROCAM e DAD (Kappa). Estimou-se a frequência de alterações metabólicas e de obtenção de metas lipídicas, pós-intervenção, segundo a IV Diretriz da Sociedade Brasileira de Cardiologia. De acordo com critérios clínicos e laboratoriais, os pacientes receberam rosuvastina e/ou ciprofibrato. O nível de significância foi estabelecido em p<5%. Utilizou-se o programa SPSS 18.0. Resultados: População predominantemente masculina (76,9%); com média de idade de 36,8 anos (desvio padrão=10,3); 66,3% em uso de TARV, dos quais 50,0% há menos de dois anos. Alto risco para DCV variou de 0,4 a 5,7%. Risco intermediário para DCV foi evidenciado em 3,2, segundo o escore de Framingham e em 39,9% dos participantes, considerando a presença de fatores agravantes. Na avaliação inicial, 72,8% dos participantes apresentavam algum tipo de dislipidemia. Observou-se uma redução significativa do percentual de indivíduos com dislipidemias mistas e com HDL-baixo, pós-implantação de metas lipídicas (p<0,05). Conclusões: Framingham com fatores agravantes parece superestimar o risco cardiovascular em pacientes HIV positivos. Um terço dos pacientes com dislipidemias alcançou as metas terapêuticas lipídicas, em seis meses. Novos estudos são necessários para avaliar o poder de predição dos diferentes escores de risco, bem como para avaliar os benefícios à médio e longo prazo do uso de hipolipemiantes, nessa população.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2016-08-17T15:19:39Z No. of bitstreams: 2 Dissertação - Lana Pacheco Franco - 2016.pdf: 2286916 bytes, checksum: 906480e497d4f4ed792e28ce7d57d9b7 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2016-08-17T15:21:10Z (GMT) No. of bitstreams: 2 Dissertação - Lana Pacheco Franco - 2016.pdf: 2286916 bytes, checksum: 906480e497d4f4ed792e28ce7d57d9b7 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2016-08-17T15:21:10Z (GMT). No. of bitstreams: 2 Dissertação - Lana Pacheco Franco - 2016.pdf: 2286916 bytes, checksum: 906480e497d4f4ed792e28ce7d57d9b7 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2016-05-03 / This study aimed to assess whether polymorphisms in the apolipoprotein E gene and food consumption are related to lipid profile of adults with Normal-Weight Obesity Syndrome. Methodology: this was an analytical cross-sectional study, including adults with Normal-Weight Obesity Syndrome. Socioeconomic, health and lifestyle questionnaires were administered. Anthropometric variables, body composition and blood pressure were evaluated. Dietary intake, lipid profile and genotyping of polymorphisms rs7412 and rs429358 in the apolipoprotein E gene were evaluated. Results: from the 115 individuals, 72.2% were women. The median age was 22.6 years (21.4 – 25.2). Only 6.0% of women and no man had increased waist circumference. No women and 6.2% of men had changes in blood pressure. When traditional lipid profile was assessed, 52.5% had dyslipidemia. When apolipoprotein concentrations were included, the prevalence was 73.0%. There was a positive relationship between the presence of allele ε2 and apolipoprotein A1 levels (ε2ε3 versus ε3ε3: β = 21.3; 95% CI = 4.2 to 38.3; p = 0.015) and between ε4 allele and apolipoprotein B (ε4 versus ε2: β = 14.8; 95% CI = 0.08 a 29.5; p = 0.049 and ε4 versus ε3: β = 9.1; 95% CI = 0.6 a 17.6; p = 0.036). Carriers of ε2 allele had 81% less chance of presenting dyslipidemia compared to ε3ε3 individuals (OR = 0.2; 95% CI = 0,04 a 0,8; p = 0.027). Associations between body fat distribution and lipid profile and between food consumption and lipid profile were observed and differed among genotypes. Conclusion: both polymorphisms in the apolipoprotein E gene and the food consumption were associated with lipid profile of adults with Normal-Weight Obese Syndrome. This was the first study to describe the apolipoprotein E genotype and to analyze relationships between genetic profile, food intake and lipid profile of subjects with Normal-Weight Obesity Syndrome. / Avaliar se polimorfismos no gene da apolipoproteína E relacionam-se com consumo alimentar e perfil lipídico de indivíduos adultos com a Síndrome do Obeso Eutrófico. Metodologia: foi realizado estudo transversal analítico, incluindo adultos com Síndrome do Obeso Eutrófico. Foram aplicados questionários socioeconômico, de saúde e estilo de vida e avaliadas variáveis antropométricas, de composição corporal e pressão arterial. Determinou-se o consumo alimentar, o perfil lipídico e o genótipo referente aos polimorfismos rs7412 e rs429358 no gene da apolipoproteína E. Resultados: dos 115 indivíduos avaliados, 72,2% eram mulheres. A mediana de idade foi de 22,6 anos (21,4 – 25,2). Apenas 6,0% das mulheres apresentaram aumento da circunferência da cintura e 6,2% dos homens, alterações na pressão arterial. Quando avaliado o perfil lipídico tradicional, 52,5% dos indivíduos apresentaram dislipidemias. Incluindo-se as concentrações de apolipoproteínas A1 e B, a prevalência foi de 73,0%. O alelo ε2 relacionou-se à maior concentração de apolipoproteína A1 (ε2ε3 versus ε3ε3: β = 21,3 IC 95% = 4,2 a 38,3 p = 0,015) e o alelo ε4, à maior concentração de apolipoproteína B (ε4 versus ε2: β = 14,8 IC 95% = 0,1 a 29,5 p = 0,049 e ε4 versus ε3: β = 9,1 IC 95% = 0,6 a 17,6 p = 0,036). Carreadores do alelo ε2 apresentaram chance 81% menor de desenvolver dislipidemia em comparação aos homozigotos ε3ε3 (OR = 0,2 IC 95% = 0,04 a 0,8 p = 0,027). Associações entre a distribuição da gordura corporal, o consumo alimentar e o perfil lipídico foram observadas e diferiram entre os genótipos. Conclusão: tanto os polimorfismos no gene da apolipoproteína E quanto o consumo alimentar foram associados ao perfil lipídico de adultos com a Síndrome do Obeso Eutrófico. Este foi o primeiro trabalho a descrever o genótipo da apolipoproteína E e a analisar suas relações com consumo alimentar e perfil lipídico nessa população.

Atherosclerosis, one major cause of morbidity and mortality worldwide, is a complex and multifactorial disease that involves three mainly conditions: chronic inflammation, dyslipidemia and oxidative stress. Although statins are the first-line therapy for LDL cholesterol (LDL-C) lowering, the efficacy of cardiovascular events prevention is limited to 30-40%. This residual risk brought attention to the need of new therapies and clinical targets beyond LDL-C, such as inflammation and oxidative stress. Importantly, suboptimal treatment and/or statin discontinuation due to adverse effects have also been a very challenging clinical problem. Complementary diet therapy can be an effective and safe approach to support pharmacological treatment, especially when drugs alone are insufficient to attenuate risk factors and/or the recommended dose is not well tolerated. The aim of this study was to evaluate the effects of three bioactive components, namely omega-3 fatty acids, plant sterols and polyphenols, on markers of dyslipidemia, inflammation and oxidative stress in patients treated with statins. A randomized, crossover clinical study was carried out, with the participation of 53 subjects. At each intervention period, study participants received a packaged for the functional or control treatment. Functional treatment consisted of fish oil (1.7 g of EPA+DHA/day), chocolate containing plant sterols (2.2 g/day) and green tea (two tea sachets/day). Control treatment consisted of soy oil softgels, regular chocolate and anise tea. After 6 weeks of intervention, functional treatment reduced plasma LDL-C (-13.7% ± 3.7, p=0.002) and C-reactive protein (-35.5% ± 5.9, p=0.027). Plasma triacylglycerol (-15.68% ± 5.94, p=0.02) and MDA (-40.98% ± 6.74, p=0.04) were reduced in subgroups of patients (n=23) with baseline values above the median (93 mg/dL and 2.23 umol/L, respectively). Analysis of lathosterol and campesterol in plasma suggested that intensity of LDL-C reduction was influenced by cholesterol absorption rate rather than its endogenous synthesis. After multivariate analysis, patients identified as \"good responders\" to supplementation (n=10) were recruited for a pilot protocol of statin dose reduction with complementary diet therapy. Responders received the functional treatment for 12 weeks: standard statin therapy was kept during the first 6 weeks and reduced by 50% from weeks 6 to 12. No difference was observed for plasma lipids and inflammation biomarkers, cholesterol efflux capacity or HDL particle number after statin dose reduction when compared to standard therapy. Although limited by the small sample size, our study demonstrates the potential for a new therapeutic approach combining lower statin dose and specific dietary compounds. This may be particularly helpful for the many patients with, and at risk for, CVD who cannot tolerate high-dose statin therapy. / A aterosclerose, uma importante causa mundial de morbidade e mortalidade, é uma doença complexa e multifatorial que envolve três principais condições: inflamação crônica, dislipidemia e estresse oxidativo. Embora as estatinas sejam fármacos de primeira linha para redução de LDL colesterol (LDL-C), sua eficácia na prevenção de eventos cardiovasculares é limitadada a 30-40%. Este risco cardiovascular residual evidencia a necessidade de novas terapias e marcadores clínicos que vão além do LDL-C, como inflamação e estresse oxidativo. Não obstante, tratamento subótimo e/ou interrupção do uso de estatinas devido à ocorrencia de efeitos adversos também é um grave obstáculo na clínica médica. Neste contexto, a terapia dietética complementar representa uma abordagem efetiva e segura para o suporte do tratamento farmacológico, especialmente quando as drogas são insuficientes para atenuar fatores de risco e/ou quando a dose recomendada não é bem tolerada. O objetivo do presente estudo foi avaliar o efeito de três compostos bioativos - ácidos graxos ômega 3, fitosteróis e polifenóis - sobre marcadores de inflamação, lipemia e estresse oxidativo em indivíduos tradados com estatinas. Foi realizado um estudo clínico randomizado, de delineamento crossover, com a participação de 53 voluntários. A cada período de intervenção, os participantes receberam um tratamento funcional ou controle. O tratamento funcional foi composto por cápsulas de óleo de peixe (1.7 g/dia de EPA+DHA), chocolate contendo fitosteróis (2.2 g/dia) e chá verde (dois sachês/dia). O tratamento controle foi composto por cápsulas de óleo de soja, chocolate sem adição de fitosteróis e chá de anis. Após 6 semanas de intervenção, o tratamento funcional reduziu a concentração plasmática de LDL-C (-13.7% ± 3.7, p=0.002) e proteína C-reativa (-35.5% ± 5.9, p=0.027). Triglicerídeos (- 15.68% ± 5.94, p=0.02) e malondialdeído (-40.98% ± 6.74, p=0.04) foram reduzidas apenas em subgrupos de indivíduos que apresentavam valores basais acima da mediana (93 mg/dL e 2.23 umol/L, respectivamente). A análise de latosterol e campesterol no plasma sugeriu que a intensidade da redução de LDL-C não foi influenciada pela síntese endógena de colesterol, mas sim pela taxa de absorção. Após análise multivariada dos resultados, pacientes identificados como \"good responders\" à suplementação (n=10) foram recrutados para um estudo piloto de redução da dosagem da estatina, aliado à terapia dietética complementar. Estes pacientes receberam o tratamento funcional por 12 semanas: durante as 6 primeiras semanas mantevese a dosagem de estatina, que em seguida foi reduzida em 50% das semanas 6 a 12. Não foram observadas diferenças para os marcadores plasmáticos de lipídeos, inflamação, capacidade de efluxo de colesterol ou número de partículas de HDL após a redução da dose de estatina, quando comparada à terapia convencional. Embora limitado pelo reduzido número de pacientes, o estudo demonstra o potencial para uma nova abordagem terapêutica, combinando reduzida dose de estatina com específicos compostos bioativos. Esta pode ser uma importante alternativa para muitos pacientes em risco cardiovascular e que são intolerantes à terapia com altas doses de estatina.

Abstract Helicobacter pylori is a Gram-negative bacterium, which infects the stomach of more than 50% of the population worldwide. In addition to being the most important risk factor for gastric cancer and peptic ulcers, H. pylori infection is a risk factor for several extra-digestive diseases including dyslipidemia. The consequences of having an H. pylori infection are significantly influenced by the inflammatory response of the host. The pattern recognition receptor Toll-like receptor 4 (TLR4) and the cytokine interleukin 6 (IL6) are important mediators of inflammation in H. pylori related diseases. We have analyzed a series of control subjects and patients with dyspepsia, peptic ulcers or gastric cancer for frequent genetic polymorphisms of the TLR4 and IL6 genes. The prevalence of H. pylori infection, the histologic features of gastritis and cancer and serum endocrine markers and lipid concentrations were also analyzed. Furthermore, the expression of TLR4 was analyzed in specific cell types of gastric mucosa by immunohistochemistry. The TLR4 wild type genotypes of polymorphisms +896 and +1196 were associated with an increased risk of peptic ulcers. The same genotypes also associated with higher serum gastrin levels, but not with atrophy or other features of gastritis. The TLR4 expression was seen in the gastrin and somatostatin secreting cells of gastric mucosa. These results suggest a regulatory link between TLR4 and gastrin secretion. Such a link indicates the presence of a novel effector mechanism for innate immunity in modifying the host endocrine function. The IL6 -174 polymorphism associated significantly with a risk of the diffuse type of gastric carcinoma but not with the intestinal type or its precursor conditions. Finally, we demonstrated that H. pylori infections modify HDL serum levels significantly only in IL6 -174 CC genotype patients, which suggests that the detrimental effects of H. pylori infections on HDL levels are transmitted through IL6. These results clarify the mechanisms of H. pylori related diseases and open new possibilities for research on peptic ulcer disease, gastric cancer and dyslipidemia. / Tiivistelmä Helicobacter pylori on yleinen ihmisen mahalaukussa esiintyvä Gram-negatiivinen bakteeri. Helikobakteeri on tärkein mahasyövän ja maha- ja pohjukaissuolihaavan riskitekijä ja se on myös muun muassa rasva-aineenvaihdunnan häiriöiden riskitekijä. Ihmisen tulehdusvaste vaikuttaa merkittävästi helikobakteeri-infektion seurauksiin. Tollin kaltainen reseptori 4 (TLR4), joka on hahmontunnistusreseptori ja tulehduksenvälittäjäaine interleukiini 6 (IL6) ovat tärkeitä ihmisen tulehdusvasteeseen osallistuvia proteiineja. Olemme tutkineet dyspepsiaa, maha- ja pohjukaissuolihaavaa ja mahasyöpää sairastavilta potilailta sekä kontrollihenkilöiltä TLR4:n ja IL6:n geenien yleisiä emäsjärjestyksen polymorfioita. Tutkimme myös helikobakteeri-infektion yleisyyttä ja histologisia piirteitä, mahasyövän histologisia piirteitä ja seerumin merkkiaineita ja lipidipitoisuuksia. Lisäksi tutkimme TLR4:n ilmenemistä mahan limakalvolla immunohistokemiallisesti. TLR4:n polymorfismien +896 ja +1196 villin tyypin genotyypit liittyivät kohonneeseen maha- ja pohjukaissuolihaavan riskiin. Samat genotyypit liittyivät myös korkeampiin gastriinitasoihin. TLR4:ä esiintyi mahalaukun limakalvolla gastriinia tai somatostatiinia ilmentävissä soluissa. Täten TLR4:n ja maha- pohjukaissuolihaavariskin yhteys näyttää välittyvän gastriinin erityksen kautta, mikä viittaa uuteen säätely-yhteyteen luontaisen immuniteetin ja mahalaukun umpieritysjärjestelmän välillä. IL6 -174 -polymorfismi yhdistyi diffuusin tyypin mahakarsinooman riskiin mutta ei intestinaalisen tyypin karsinooman riskiin. Helikobakteeri-infektio yhdistyi pienentyneisiin HDL-kolesterolipitoisuuksiin vain potilailla, joilla oli IL6 -174 CC genotyyppi, mikä viittaa helikobakteerin kolesterolitasoille haitallisen vaikutuksen välittyvän IL6:n kautta. Nämä tulokset antavat lisätietoa helikobakteerin aiheuttamien sairauksien mekanismeista ja avaavat uusia tutkimuspolkuja myös mahahaavan, mahasyövän ja rasva-aineenvaihdunnan häiriöiden kliiniseen tutkimukseen.

Dyslipidemia can be a comorbidity of both insulin-resistance and atherosclerosis. Hypertriglyceridemia is common in hyperglycemia and is associated with hypoalphalipoproteinemia (low HDL) and with altered nucleotide or purinergic signaling. We therefore hypothesized that extracellular nucleotides may affect hepatic lipoprotein metabolism. Our studies confirm this view and show that nucleotides regulate cellular proteolytic pathways in liver cells and thereby control lipoprotein secretion and their metabolism by hepatic lipase (HL). Treatment of liver cells with the nucleotide, adenosine diphosphate (ADP), stimulates VLDL-apoB100 and apoE secretion, but blocks HDL-apoA-I and HL secretion. ADP functions like a proteasomal inhibitor to block proteasomal degradation and stimulate apoB100 secretion. Blocking the proteosome is known to activate autophagic pathways. The nucleotide consequently stimulates autophagic degradation in liver cells and increases cellular levels of the autophagic proteins, LC3 and p62. Confocal studies show that ADP increases cellular LC3 levels and promotes co-localization of LC3 and apoA-I in an autophagosomal degradation compartment. ADP acts through the G-protein coupled receptor, P2Y13, to stimulate autophagy and block both HDL and HL secretion. Overexpression of P2Y13 increases cellular LC3 levels and blocks the induction of both HDL and HL secretion, while P2Y13 siRNA reduce LC3 protein levels and cause up to a ten-fold stimulation in HDL and HL secretion. P2Y13 gene expression regulates autophagy through the insulin receptor (IR-β). A reduction in P2Y13 expression increases the phosphorylation of IR-β and protein kinase B (Akt) >3-fold, while increasing P2Y13 expression inhibits the activation of IR-β and Akt. Experiments with epitope-labeled apoA-I and HL show that activation of purinergic pathways has no effect on the internalization and degradation of extracellular apoA-I and HL, which confirms the view that nucleotides primarily impact intracellular protein transport and degradation. In conclusion, elevated blood glucose levels may promote dyslipidemia by stimulating purinergic signaling through P2Y13 and IR-β and perturbing the intracellular degradation and secretion of both HDL and VLDL.

L'obésité est une maladie multifactorielle qui constitue un facteur de risque de nombreuses pathologies, notamment les maladies cardiovasculaires, le diabète et les maladies neurodégénératives. Des études épidémiologiques récentes suggèrent un effet obésogène des contaminants environnementaux, mais peu d'informations sont disponibles sur leur effet potentiel sur le métabolisme des lipoprotéines hépatiques. L'objectif de cette étude était de déterminer l'effet de polluants environnementaux de la famille des hydrocarbures aromatiques polycycliques (HAP) sur trois récepteurs des lipoprotéines, le récepteur des LDL (LDL-R), le lipolysis-stimulated lipoprotein receptor (LSR) et le scavenger receptor B1 (SR-B1) ainsi que sur les ATP binding cassette transporter A1 (ABCA1) et G1 (ABCG1) en utilisant des modèles cellulaires et/ou animaux. Les études par immunoblots et immunofluorescence in vitro ont révélé que l'exposition de cellules Hepa1-6 au B[a]P diminue de manière significative les taux de protéine LSR, LDL-R et ABCA1, alors qu’aucune modification significative du taux et de l’activité du LSR n’a été observée lors d’une exposition au pyrène ou au phénanthrène. L’analyse en temps réel par PCR et les études avec la lactacystine ont révélé que cet effet était dû principalement à une augmentation de la dégradation par le protéasome plutôt qu’à une diminution de la transcription ou à une augmentation de la dégradation lysosomale. En outre, les ligand-blots ont révélé que les lipoprotéines exposées au B[a]P avaient une affinité réduite pour le LSR ou le LDL-R. Des souris C57Bl/6RJ ont été traitées par le B[a]P (0,5 mg / kg, i.p) toutes les 48 h pendant 15 jours. Le gain de poids observé est accompagné d’une augmentation des taux de triglycérides et de cholestérol plasmatiques, du taux de cholestérol hépatique, et d’une diminution du taux de LDL-R et ABCA1 chez animaux traités au B[a]P par rapport aux témoins. Les corrélations observées entre les taux de LSR et de LDL-R hépatiques chez les souris contrôle ne sont plus observées chez les souris traitées au B[a]P, ce qui suggère un dérèglement du métabolisme des lipoprotéines hépatiques. Ces résultats suggèrent que la prise de poids induite par le B[a]P est peut-être liée à son action inhibitrice sur le LSR et le LDL-R, ainsi que sur l’ABCA1 et le métabolisme des lipoprotéines hépatiques, ce qui conduit à un statut lipidique modifié chez les souris traitées au B[a]P, donnant ainsi un nouvel éclairage sur les mécanismes sous-jacents de la contribution des polluants tels que le B[a]P à la perturbation de l'homéostasie lipidique, susceptible de contribuer à la dyslipidémie associée à l'obésité / Obesity is a multifactorial disorder that represents a significant risk factor for many pathologies including cardiovascular diseases, diabetes and neurodegenerative diseases. Recent epidemiological studies suggest potential obesogenic effects of environmental contaminants, but little information is available on their potential effect on hepatic lipoprotein metabolism. The objective of this study was to determine the effect of the common environmental pollutants, belonging to polycyclic aromatic hydrocarbon (HAP) on three lipoprotein receptors, the LDL-receptor (LDL-R), the scavenger receptor B1 (SRB1) and the lipolysis-stimulated lipoprotein receptor (LSR) as well as the ATP binding cassette transporters A1 (ABCA1) and G1 (ABCG1) using cell and/or animal models. Immunoblot and immunofluorescence in vitro studies revealed that exposure of Hepa1-6 to benzo[a]pyrene (B[a]P) significantly decreased LSR, LDL-R and ABCA1 protein levels, whereas no significant changes in protein levels and LSR activity where observed upon cell treatment with pyrene or phenanthrene. Real-time PCR analysis, lactacystin and chloroquine studies revealed that this effect was due primarily to increased proteasome-mediated degradation rather than to decreased transcription or to increased lysosomal degradation. Furthermore, ligand blots revealed that lipoproteins exposed to B[a]P displayed markedly decreased binding to LSR or LDL-R. C57Bl/6RJ mice were treated with B[a]P (0.5 mg/kg, i.p) every 48 h for 15 days. The increased weight gain observed was accompanied by increased plasma triglycerides and cholesterol levels, increased liver cholesterol content, and decreased LDL-R, ABCA1, ABCG1 and SR-B1 protein levels in B[a]P-treated animals as compared to controls. Correlations observed between hepatic LSR and LDL-R levels in control mice were no longer observed in B[a]P treated mice, suggesting a potential dysregulation of hepatic lipoprotein metabolism.Taken together, these results suggest that B[a]P-induced weight gain may be due its inhibitory action on LSR and LDL-R, as well as ABCA1 and lipoprotein metabolism in the liver, which leads to the modified lipid status in B[a]P-treated mice, thus providing new insight into mechanisms underlying the involvement of pollutants such as B[a]P in the disruption of lipid homeostasis, potentially contributing to dyslipidemia associated with obesity

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2015-07-27T13:13:00Z No. of bitstreams: 1 Tercio Lemos de Morais.pdf: 1272228 bytes, checksum: ed3fb7d1f441b1f6ede36571fcb2cb7a (MD5) / Made available in DSpace on 2015-07-27T13:13:00Z (GMT). No. of bitstreams: 1 Tercio Lemos de Morais.pdf: 1272228 bytes, checksum: ed3fb7d1f441b1f6ede36571fcb2cb7a (MD5) Previous issue date: 2014-02-21 / Evidence suggests the association of combined oral contraceptives (COC) with the development of hypertension, metabolic dysfunction and cardiovascular risk. The mechanisms involved in such association are not fully understood. It was demonstrated in previous studies by our group that there is an autonomic modulation imbalance before the development of hypertension in people with a positive family history of hypertension. This project evaluates the impact of combined oral contraceptives on anthropometric (BMI, abdominal circumference), hemodynamic (blood pressure, heart rate, cardiac outflow and total peripheral resistance), metabolic (serum glucose, total cholesterol and triglycerides) and autonomic (serum cathecolamines, heart rate variability) in normotensive and in hypertensive women (18 to 35 years of age) under combined oral contraceptives. We did not observe any significant change in blood pressure, hemodynamic and autonomic variables in the normotensive group under second and third generation of combined oral contraceptives. The same with hypertensive women under drospirenona (DRSP) and etinilestradiol (EE). Concerning the metabolic variables (against the control group), the normotensive women under combined oral contraceptives showed an increase in both means of total cholesterol (165.95 ± 29.21 vs 189.11 ± 28.96) and triglycerides (72.62 ± 23.44 vs 110.07 ± 40.60). Hypertensive women under DRSP+EE had also a significant increase in triglycerides when comparing basal (72.62 ± 23.44 vs 110.07 ± 40.60) with the later 6 month period( 72.62 ± 23.44 vs 110.07 ± 40.60). Moreover, in this same group of hypertensive women under Drospirenone-containing oral contraceptive, no change was found in potassium levels, the aldosterone-renin-angiotensin system or pharmacological interactions with anti-hypertensive drugs. Our conclusion is that second and third generation combined hormonal oral contraceptives causes no significant change in blood pressure or hemodynamic and autonomic variables. Also, DRSP+EE demonstrates a safe profile when used by young hypertensive women under anti-hypertensive drugs. No detectable variations in blood pressure and neuro-humoral activation, no hydro electrolyte imbalance and no metabolic change (except for a slight triglycerides augmentation) was encountered. / Existem evidências da associação entre uso de contraceptivo hormonal oral combinado (CHOC) com o desenvolvimento de hipertensão arterial, distúrbios metabólicos e risco cardiovascular. Os mecanismos envolvidos ainda não estão totalmente elucidados. Estudos prévios do nosso grupo demonstraram que há um desequilíbrio na modulação autonômica, mensurada pela análise da variabilidade da frequência cardíaca, antecedendo o desenvolvimento de HAS em filhos de hipertensos. No presente projeto, avaliamos o impacto do uso de CHOC em parâmetros antropométricos (índice de massa corpórea, circunferncia abdominal), hemodinâmicos (pressão arterial, frequencia cardíaca, débito cardíaco e resistência vascular periférica), metabólicos (glicemia, colesterol total e triglicérides), e autonômicos (dosagem sérica de noradrenalina e variabilidade da frequência cardíaca) em mulheres normotensas e hipertensas usuárias e não usuárias de CHOC, na faixa etária de 18 a 35 anos de idade. Como resultados, não observamos mudanças significativas na pressão arterial, variáveis hemodinâmicas e autonômicas na coorte de mulheres normotensas usuárias e não usuárias de CHOC de segunda e terceira geração, bem como no estudo prospectivo de mulheres hipertensas usuárias de drospirenona (DRSP) mais etinilestradiol (EE). Com relação às variáveis metabólicas, comparado ao grupo controle, a coorte de mulheres normotensas usuárias de CHOC apresentou valores médios de colesterol total (165,95 ± 29,21 vs 189,11 ± 28,96) e triglicérides (72,62 ± 23,44 vs 110,07 ± 40,60) superiores aos observados no grupo das não usuárias. As mulheres hipertensas usuárias de DRSP+EE, também apresentaram valores médios de triglicérides superiores estatisticamente significantes comparado ao momento inicial (124,3 ± 57,7 vs 174,7 ± 70,6), respectivamente basal e após 6 meses. Ainda no grupo de hipertensas, o uso de CHOC contendo drospirenona não se associou a mudanças na atividade do sistema renina angiotensina aldosterona, não alterou os níveis séricos de potássio, nem apresentou interações medicamentosas com medicamentos anti-hipertensivos usados. Concluímos que o uso de CHOC de segunda e terceira geração não causou alterações significativas na pressão arterial, parâmetros hemodinâmicos e autonômicos, com modesto impacto negativo sobre o perfil lipídico. E a DRSP+EE apresenta um perfil seguro quando usado como contraceptivo num grupo de mulheres hipertensas jovens já em uso de anti-hipertensivos, considerando-se que: não foram detectadas variações nos valores de pressão aretrial e de ativação neuro-humoral, não ocorreram distúrbios hidro eletrolíticos, e nem alterações em parâmetros metabólicos, execeto um leve aumento nos níveis de triglicérides.

Le syndrome de chylomicronémie multifactorielle (MCS) est une maladie complexe au cours de laquelle les valeurs de triglycérides (TG) dépassent 10 mmol/L. Le MCS se manifeste à l'âge adulte et a une prévalence d’environ 1 adulte sur 600 au Québec. Deux conditions doivent être réunies pour développer cette maladie : une composante génétique (oligogénique ou polygénique) ainsi que la présence de facteurs de risque reliés au style de vie (une alimentation riche en gras et en sucres raffinés, une consommation excessive d'alcool, un diabète non contrôlé ou l'obésité). Le MCS est une condition de santé grave, puisqu’il augmente considérablement le risque de pancréatites aigües et peut doubler le risque de maladies cardiovasculaires. Actuellement, il n’y a pas d’étude d’intervention nutritionnelle, réalisée dans cette population, qui permette de connaitre l’approche nutritionnelle la plus bénéfique. Ce mémoire présente les résultats d’une étude croisée randomisée dont l’objectif était d’évaluer l’impact d’une diète faible en lipides et d’une diète faible en glucides sur le profil lipidique à jeun et postprandial chez des patients atteints de MCS en fonction de la présence d’un variant rare à l’état hétérozygote du gène de la lipoprotéine lipase (LPL). Les résultats de cette étude suggèrent qu’une diète faible en lipides permettrait une diminution plus importante des TG chez les sujets porteurs d’un variant rare à l’état hétérozygote de la LPL et pourrait ultimement contribuer à réduire le risque de pancréatite aigüe sur le long terme. / Multifactorial chylomicronemia syndrome (MCS) is a complex disease in which triglyceride (TG) values exceed 10 mmol/L. MCS occurs in adulthood and has a prevalence of approximately 1 in 600 adults in Quebec. Two conditions must be met to develop this disease: a genetic component (oligogenic or polygenic) as well as the presence of lifestyle risk factors (a diet high in fat and refined sugars, excessive alcohol consumption, uncontrolled diabetes or obesity). MCS is a serious health condition, as it significantly increases the risk of acute pancreatitis and can double the risk of cardiovascular disease. Currently, there are no nutritional intervention studies conducted in this population to determine the most beneficial nutritional approach. This thesis presents the results of a randomized crossover study whose objective was to evaluate the impact of a low-fat diet and a low-carbohydrate diet on the fasting and postprandial lipid profile in patients with SCD according to the presence of a rare heterozygous lipoprotein lipase (LPL) gene variant. The results of this study suggest that a low-fat diet would result in a greater reduction in TGs in subjects with a rare heterozygous variant of LPL and may ultimately help reduce the risk of acute pancreatitis in the long term.