CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior / As dislipidemias e o diabetes apresentam-se como importantes fatores de risco nas doenÃas cardiovasculares. Quando se associa ao estresse oxidativo podem acelerar a progressÃo das lesÃes aterosclerÃticas. Estudos com produtos naturais fornecem dados interessantes no controle dessas doenÃas. No presente estudo foram utilizados dois compostos derivados da canela, o Ãcido cinÃmico (AC) e cinamato de metila (CM), semelhantes estruturalmente e com atividades biolÃgicas e farmacolÃgicas jà descritas. O presente estudo tem por objetivo avaliar os possÃveis efeitos hipolipidÃmico e hipoglicÃmico, bem como o potencial antioxidante do Ãcido cinÃmico e do cinamato de metila em protocolos experimentais de dislipidemias e diabetes induzidas farmacologicamente. A hiperlipidemia foi induzida em camundongos machos atravÃs de dois protocolos agudos, mediante uma Ãnica administraÃÃo intraperitoneal de 400mg/Kg de Triton WR-1339 e 400mg/Kg de Poloxamer-407 em todos os animais, exceto no controle negativo. Os grupos foram tratados via oral por gavagem, onde o controle negativo e o controle positivo receberam Ãgua potÃvel de acordo com o peso, o grupo fenofibrato recebeu a dose de 200mg/Kg, enquanto que os grupos Ãcido cinÃmico e cinamato de metila receberam a mesma dose de 20mg/Kg. O sangue desses animais foi coletado em 24 e 48 horas apÃs as induÃÃes e foram verificados os nÃveis plamÃticos de colesterol total, triglicerÃdeos, glicose, AST e ALT. ApÃs a coleta de 48 horas retirou-se o tecido hepÃtico, em ambos os protocolos, para analisar a peroxidaÃÃo lipÃdica, atravÃs da determinaÃÃo dos grupos sulfidrÃlicos nÃo-proteÃcos (NP-SH), malondialdeÃdo (MDA) e das enzimas antioxidantes: superÃxido dismutase (SOD) e catalase (CAT). Para determinar o potencial hipoglicemiante do Ãcido cinÃmico e do cinamato de metila utilizou-se o protocolo de diabetes induzida por aloxano atravÃs de uma Ãnica injeÃÃo intraperitoneal na dose de 200mg/Kg. Os grupos foram tratados por sete dias com Ãgua potÃvel de acordo com o peso (grupo controle positivo), metformina 50mg/Kg (grupo metformina), Ãcido cinÃmico 20mg/Kg (grupo Ãcido cinÃmico) e cinamato de metila 20mg/Kg (grupo cinamato de metila). Observou-se que, apÃs a induÃÃo, tanto com o Triton quanto Poloxamer, o AC e o CM foram capazes de reduzir o colesterol e os triglicerÃdeos apÃs 24 e 48 horas, sem, no entanto alterar as enzimas hepÃticas AST e ALT. Somado a esse fator observou-se que as substÃncias em estudo apresentaram certa atividade sobre o estresse oxidativo tendo em vista a reduÃÃo do MDA e NP-SH no protocolo do Triton e da NP-SH no protocolo do poloxamer. Tendo o cinamato de metila apresentado uma maior atividade em comparaÃÃo ao Ãcido cinÃmico na anÃlise de 48 horas apÃs a induÃÃo em ambos os protocolos. Observando a resposta do AC e o CM em protocolo de induÃÃo de diabetes por aloxano, constatou-se que as referidas substÃncias foram capazes de reduzir de forma semelhante, a glicemia dos animais. Os resultados obtidos mostraram o potencial terapÃutico do AC e CM no tratamento das dislipidemias e do diabetes, no entanto faz necessÃrios novos estudos em protocolos crÃnicos que possam garantir a seguranÃa e eficÃcia de sua utilizaÃÃo. / Dyslipidemia and diabetes are presented as important risk factors in cardiovascular disease. When is associated with oxidative stress may accelerate the progression of atherosclerotic lesions. Studies with natural products provide interesting data in the control of these diseases. In the present study two compounds cinnamon derivatives, cinnamic acid (CA) and methyl cinnamate (MC) and structurally similar biological and pharmacological activities already described above were used. The present study aims to evaluate the possible hypolipidemic and hypoglycemic effects as well as the antioxidant potential of cinnamic acid and methyl cinnamate in experimental protocols pharmacologically induced dyslipidemia and diabetes. Hyperlipidemia was induced in male mice by two acute protocols through a single intraperitoneal administration of 400mg/kg Triton WR -1339 and 400mg/kg Poloxamer -407 in all animals except the negative control. The groups were treated orally by gavage, where the positive control and the negative control received drinking water according to the weight of fenofibrate group received 200mg/kg, whereas the cinnamic acid, methyl cinnamate groups and received the same dose 20mg/kg. The blood of these animals was collected at 24 and 48 hours after induction and was plamÃticos checked the levels of total cholesterol, triglycerides, glucose, AST and ALT. After collecting 48 hours we removed the liver tissue , in both protocols , to analyze lipid peroxidation , through the determination of non-protein sulfhydryl groups ( NP -SH ) , malondialdehyde ( MDA ) and antioxidant enzyme : superoxide dismutase (SOD ), and catalase (CAT). To determine the hypoglycemic potential of cinnamic acid and methyl cinnamate was used protocol alloxan induced diabetic by a single intraperitoneal injection at 200mg/kg. Both groups were treated for 7 days with drinking water according to the weight (positive control group), 50mg/Kg metformin (metformin group), cinnamic acid 20mg/kg (cinnamic acid group) and methyl cinnamate 20mg/kg (group cinamto methyl). It was observed that after induction with either Poloxamer as Triton, AC and BC were able to reduce cholesterol and triglycerides after 24 and 48 hours, without changing the liver enzymes AST and ALT. Added to this factor was observed that the substance under study showed some activity on oxidative stress in order to reduce the MDA and NP -SH in the protocol of the Triton and NP -SH in the poloxamer protocol. Having methyl cinnamate presented higher activity compared to cinnamic acid analysis 48 hours after the induction of both protocols. Observing the response of the CM and the AC induction protocol in alloxan diabetes, it was found that these compounds were able to similarly reduce the glucose levels. The results showed the therapeutic potential of CA and CM in the treatment of dyslipidemia and diabetes, however does require new studies in chronic protocols that can ensure the safety and efficacy of its use.

La stéatose hépatique non-alcoolique (NAFLD) est l’affection hépatique chronique la plus fréquente à l’heure actuelle dans le monde industrialisé car fortement liée au développement du syndrome métabolique et des dyslipidémies associées. À ce jour, les mécanismes de la pathologie restent mal définis et les moyens thérapeutiques disponibles ont une efficacité modérée. Des études épidémiologiques ont rapporté un effet bénéfique de la consommation de thé pour lutter contre les désordres hépatiques et les facteurs de risque cardiovasculaires tel que la dyslipidémie. Cependant, les mécanismes par lesquels le thé atténue la stéatose hépatique et la dyslipidémie restent méconnus. Par conséquent, l’objectif de ce travail de thèse était d’évaluer les effets et les mécanismes d’action d’un mélange de thés vert, oolong et Pu-erh, le thé Hao Ling, sur la NAFLD et la dyslipidémie, à travers deux approches, l’une sur modèle cellulaire et l’autre sur modèle animal.Les résultats ont permis de mettre en évidence que le thé Hao Ling permettait de diminuer la lipogenèse hépatique in vitro et in vivo et ainsi d’atténuer la stéatose induite par un régime hyperlipidique et riche en saccharose chez le rat Wistar. Nous avons observé que ce thé permettait d’améliorer le profil lipidique sanguin en augmentant le taux de HDL plasmatique. Nous avons également pu mettre en évidence que le thé possédait des propriétés antioxydantes et hépato-protectrices permettant de lutter contre un inducteur de stress oxydant in vitro et de diminuer la peroxydation lipidique in vivo. Enfin, nous avons démontré que le stress oxydant "per se" entraînait une accumulation de lipides intracellulaires sur hépatocytes isolés et que le thé, grâce à ses propriétés antioxydantes, prévenait ce phénomène. Le thé Hao Ling constitue une bonne approche nutritionnelle dans la prévention de la NAFLD et dans le maintien du rapport LDL-Cholestérol/HDLCholestérol. / Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in industrializedcountries because being strongly associated with the development of metabolic syndrome and relateddyslipidemia. To date, the mechanisms of pathology remain poorly defined and available therapeutic meanshave moderate efficacy. Epidemiological studies have reported a beneficial effect of tea consumption in thefight against liver disorders and cardiovascular risk factors such as dyslipidemia. However, the mechanismsby which a blend of green tea, oolong tea and Pu-erh tea, Hao Ling tea, reduces fatty liver and dyslipidemiaremain unknown. Therefore, the objective of this thesis was to evaluate the effects and mechanisms of actionof Hao Ling tea on NAFLD and dyslipidemia, through two approaches, one on cellular model and the other onanimal model. Our results show that Hao Ling tea reduces the hepatic lipogenesis in vitro and in vivo and thusattenuates steatosis induced by a high fat-high sucrose diet in a rat model. We observed that this tea improvesthe blood lipid profile by increasing plasma HDL levels. We were also able to highlight that tea ownsantioxidant and hepato-protective properties to counteract an inducer of oxidative stress in vitro and todecrease lipid peroxidation in vivo. Finally, we have shown that the oxidative stress per se resulted in anaccumulation of intracellular lipid in isolated hepatocytes and that the tea, due to its antioxidant properties,prevented this phenomenon. The Hao Ling tea is a good nutritional approach in preventing NAFLD and tomaintain LDL/HDL ratio.

The present study investigated the longitudinal relationships between traditional, non-traditional, HIV and HAART-related risk factors and dyslipidemia in people who are living with HIV living in Nova Scotia. A total of 303 men and 39 women who were patients of the Halifax HIV clinic with at least two measurements of: total cholesterol, low density lipoprotein- cholesterol (LDL-C), high density lipoprotein- cholesterol (HDL-C) or triglyceride concentration, taken between 1997 and 2009 were included in this study. Univariate repeated measures linear mixed effects regression models were developed for men and women separately and multivariate models were developed for men. BMI, produced a significant independent effect on total cholesterol to HDL-C ratio in men living with HIV. Hepatitis C co-infection, a history of injection drug use, and viral load (copies HIV RNA/ ml blood), all found to produce significant independent effects on HDL-C concentration among men living with HIV.

Orientador: Paulo Câmara Marques Pereira / Banca: Domingues Alves Meira / Banca: Sueli Aparecida Calvi / Banca: Alcyone Artioli Machado / Banca: Jacqueline Pontes Monteiro / Resumo: O advento da utilização da terapia antiretroviral de alta atividade (HAART), a partir de 1996, representou um profundo impacto na história natural da infecção pelo HIV, promovendo uma importante e sustentada supressão na replicação viral, elevando a sobrevida e a qualidade de vida dos pacientes soropositivos. No entanto, gradualmente, foi se observando que a terapia antiretroviral é acompanhada de alterações metabólicas, como dislipidemia, principalmente hipertrigliceridemia, resistência insulínica, hiperglicemia e lipodistrofia, isto é, redistribuição da gordura corporal. Ensaios epidemiológicos demonstram correlação entre os níveis elevados de triglicerídeos (TG) e maior incidência de doença arterial coronariana (DAC). Autores sugerem a intervenção dietética como parte do tratamento da hiperlipidemia, incluindo aumento da ingestão de fibra solúvel (10g-25g/dia). Há estudos demonstrando que tanto o colesterol quanto os triglicerídeos séricos diminuem com a utilização de fibra alimentar. Alguns observaram redução apenas nos níveis séricos de triglicerídeos, enquanto que outros não verificaram alteração no metabolismo lipídico. O objetivo do presente estudo foi avaliar o efeito da fibra solúvel (goma guar parcialmente hidrolisada) suplementar sobre a hipertrigliceridemia e o perfil imunológico de indivíduos HIV positivo em tratamento com HAART. Foram estudados 19 pacientes HIV positivo com hipertrigliceridemia (níveis séricos ³ 150 a < 500mg/dL), sendo 63,16% do sexo masculino e 36,84% feminino, com média de idade de 43,52 ± 9,22 anos. Esses indivíduos utilizavam o mesmo esquema HAART há pelo menos seis meses, sem mudança da terapia durante o estudo e receberam 20g de fibra solúvel por dia, durante quatro meses... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The advent of highly active antiretroviral therapy (HAART), since 1996, represented a profound impact on the natural history of HIV-infection by promoting important and sustainable viral replication suppression and increasing survival and quality of life among seropositive patients. Nonetheless, antiretroviral therapy has been observed to be accompanied by metabolic alterations such as dyslipidemia, especially hypertriglyceridemia, insulin resistance, hyperglycemia and lipodystrophy (body fat redistribution). Epidemiological studies have demonstrated a correlation between high triglyceride (TG) levels and higher incidence of coronary artery disease (CAD). Some investigators suggest dietary intervention as part of hyperlipidemia treatment, including an increase in soluble fiber intake (10-25g/day). Whereas some studies have demonstrated that both cholesterol and serum triglyceride levels decrease with the use of food fiber, others have shown just a serum triglyceride decrease, and others failed to observe any alteration in lipid metabolism. The purpose of this study was to assess the effect of soluble fiber® (partially hydrolyzed guar gum) supplementation on hypertriglyceridemia and immune profile in HIV-positive individuals on HAART. Nineteen HIV-positive individuals with hypertriglyceridemia (serum levels 150 to < 500 mg/dL) were studied. Of these individuals, 63,16% were males and 36,84% females, with mean age of 43,52 ± 9,22 years. These individuals had been on the same HAART regimen for at least 6 months, had no change in therapy during the study and received 20g/day of soluble fiber for four months at pre-established times. Clinical-nutritional, biochemical (total proteins, albumin, globulin, total cholesterol, LDL-c, HDL-c, TG, TG/HDL-c and LDL-c/HDL-c)... (Complete abstract click electronic access below) / Doutor

Class of 2016 Abstract / Objectives: The goals of this study were: to assess patients’ knowledge of grapefruit interactions when taking statin class (dyslipidemia) medications, to identify any pertinent demographic characteristics that may influence knowledge of grapefruit statin interactions, and to identify patient preferred sources of health information. Methods: Questionnaires were administered at community health fairs during the academic school year 2014 through 2015. The survey addressed grapefruit consumption, frequency and amount, for both whole fruit and juice; examined knowledge of the potential for harmful interactions of grapefruit juice with statin medications; and how or where the participant learned this information. Results: A total of 74 participants completed surveys, of which, 72 submitted fully completed surveys, mean age was 64 (SD=+/- 15.6), 71.2% were female (N=52), and 78.1% were white. Of those surveyed, 63.5% (N= 47) reported consuming grapefruit in the past 12 months, and 36.1% (N=26) reported taking a statin. Those taking statins, 50% (N=13) reported consuming grapefruit as well. The majority of people, 61.3% (N=45), reported obtaining health related information from healthcare sources. Those with a college education were more likely to have consumed grapefruit in the last 12 months (X2=4.88, p=0.027) and to have ever consumed grapefruit (X2 =4.40, p=0.036). Conclusions: The majority of the health fair attendees surveyed were highly educated, reported having health insurance, had consumed grapefruit in the past year, and had heard about grapefruit-drug interactions.

Postprandial overproduction of apolipoprotein B48 (apoB48)-containing lipoproteins has been observed in states of insulin resistance and is important to the sequelae of cardiovascular disease, but little is understood about factors that regulate their secretion. The glucagon-like peptides (GLPs) are released from ileal enteroendocrine L-cells following lipid ingestion. I hypothesized that the GLPs could acutely affect the production of apoB48-containing triglyceride (TG)-rich lipoproteins (TRL) in the small intestine. Using the Syrian golden hamster, I first characterized the gross effects of the GLPs on TRL secretion in response to an oral fat load and then continued to dissect the mechanisms of these changes using primary intestinal cell cultures and a variety of knockout mouse models. An exogenous GLP-1 receptor (GLP-1R) agonist was found to acutely inhibit chylomicron secretion in both hamsters and mouse models, and extending the bioactivity of endogenously-secreted GLP-1 with a dipeptidyl peptidase-4 inhibitor had suppressive effects in insulin-resistant fructose-fed hamsters. The insulinotropic and delayed gastric emptying functions do not completely account for the hypolipidemic effect of GLP-1R agonism, and the effect of the GLP-1R agonist exendin-4 could be seen directly in the apoB48 secretion of primary enterocytes. In contrast, the sister peptide GLP-2 was a potent acute stimulator of chylomicron secretion in hamsters and mice. The hyperlipidemic effect of GLP-2 could be attributed to an increased rate of luminal FA uptake mediated by the posttranslational modification of the FA transporter CD36, and CD36-deficient mice were found to be refractory to the stimulatory effects of GLP-2. The activity of nitric oxide synthase was also found to be essential to the hyperlipidemic action of GLP-2. I identified a set of intercellular communications that could contribute in mediating the action of GLP-2, in which GLP-2 secreted from the enteroendocrine L-cell stimulates intestinal subepithelial myofibroblasts to release vascular endothelial growth factor, which directly activated the enterocyte to secrete apoB48. In summary, this thesis demonstrates that two co-secreted postprandial hormones have considerable but completely opposite influences on chylomicron production. Changing the balance of the GLPs’ actions in vivo could provide a therapeutic strategy to combat postprandial dyslipidemia.

The metabolic syndrome is a collection of pathologies including dyslipidemia, obesity and insulin resistance. A thorough understanding of the mechanisms behind metabolic syndrome development would help in the development of treatment and prevention strategies. Our lab has previously shown that cholesterol feeding exacerbates features of the metabolic syndrome in high fat-, high fructose-fed mice. The nuclear receptor Liver X Receptor (LXR), a master transcriptional regulator of cholesterol, fat and carbohydrate metabolism in the liver, is endogenously activated by oxysterols, metabolic derivatives of cholesterol. In order to determine whether cholesterol exerts its metabolic effects via LXR activation, parallel studies were conducted comparing chronic cholesterol supplementation with LXR activation in the hamster. Results showed that cholesterol feeding and LXR activation caused similar dyslipidemia, glucose intolerance and upregulation of target mRNA and proteins. These data support the hypothesis that the dyslipidemic effects of dietary cholesterol are mediated at least in part by LXR.

Postprandial overproduction of apolipoprotein B48 (apoB48)-containing lipoproteins has been observed in states of insulin resistance and is important to the sequelae of cardiovascular disease, but little is understood about factors that regulate their secretion. The glucagon-like peptides (GLPs) are released from ileal enteroendocrine L-cells following lipid ingestion. I hypothesized that the GLPs could acutely affect the production of apoB48-containing triglyceride (TG)-rich lipoproteins (TRL) in the small intestine. Using the Syrian golden hamster, I first characterized the gross effects of the GLPs on TRL secretion in response to an oral fat load and then continued to dissect the mechanisms of these changes using primary intestinal cell cultures and a variety of knockout mouse models. An exogenous GLP-1 receptor (GLP-1R) agonist was found to acutely inhibit chylomicron secretion in both hamsters and mouse models, and extending the bioactivity of endogenously-secreted GLP-1 with a dipeptidyl peptidase-4 inhibitor had suppressive effects in insulin-resistant fructose-fed hamsters. The insulinotropic and delayed gastric emptying functions do not completely account for the hypolipidemic effect of GLP-1R agonism, and the effect of the GLP-1R agonist exendin-4 could be seen directly in the apoB48 secretion of primary enterocytes. In contrast, the sister peptide GLP-2 was a potent acute stimulator of chylomicron secretion in hamsters and mice. The hyperlipidemic effect of GLP-2 could be attributed to an increased rate of luminal FA uptake mediated by the posttranslational modification of the FA transporter CD36, and CD36-deficient mice were found to be refractory to the stimulatory effects of GLP-2. The activity of nitric oxide synthase was also found to be essential to the hyperlipidemic action of GLP-2. I identified a set of intercellular communications that could contribute in mediating the action of GLP-2, in which GLP-2 secreted from the enteroendocrine L-cell stimulates intestinal subepithelial myofibroblasts to release vascular endothelial growth factor, which directly activated the enterocyte to secrete apoB48. In summary, this thesis demonstrates that two co-secreted postprandial hormones have considerable but completely opposite influences on chylomicron production. Changing the balance of the GLPs’ actions in vivo could provide a therapeutic strategy to combat postprandial dyslipidemia.

The metabolic syndrome is a collection of pathologies including dyslipidemia, obesity and insulin resistance. A thorough understanding of the mechanisms behind metabolic syndrome development would help in the development of treatment and prevention strategies. Our lab has previously shown that cholesterol feeding exacerbates features of the metabolic syndrome in high fat-, high fructose-fed mice. The nuclear receptor Liver X Receptor (LXR), a master transcriptional regulator of cholesterol, fat and carbohydrate metabolism in the liver, is endogenously activated by oxysterols, metabolic derivatives of cholesterol. In order to determine whether cholesterol exerts its metabolic effects via LXR activation, parallel studies were conducted comparing chronic cholesterol supplementation with LXR activation in the hamster. Results showed that cholesterol feeding and LXR activation caused similar dyslipidemia, glucose intolerance and upregulation of target mRNA and proteins. These data support the hypothesis that the dyslipidemic effects of dietary cholesterol are mediated at least in part by LXR.

ABSTRACT SANDRA C. METCALF Associations of Youth Weight Status Categories and Cholesterol Levels: Analysis of Data from the National Health and Nutrition Examination Survey (NHANES) (Under the direction of RODNEY LYN, PhD, Assistant Professor) Obesity is recognized as a risk factor for dyslipidemia, however studies specific to overweight youth and dyslipidemia are scarce. Nonetheless, expert bodies have established BMI at the 85th percentile or greater as the threshold for “at risk” in youth and advocate for lipid screening. This study analyzed associations of weight categories and occurrence of dyslipidemia among a multi-racial sample of youth 6 to 18 years of age. In this NHANES cohort, overweight youth were at significant increased risk of dyslipidemias of total cholesterol, high-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol. Obese children and adolescents demonstrated even higher risk. This study supports the hypothesis that overweight youth are at increased risk for dyslipidemia. Despite the increased risk, test agreement for overweight and dyslipidemia was poor. BMI at the 85th percentile did not provide good discrimination in detecting children with dyslipidemia and use of this threshold warrants further review.