La déficience partielle en lipoprotéine lipase (LPLD) est associée à une augmentation du risque cardiométabolique chez les hommes et les femmes. L’adiponectine, le syndrome métabolique et la ménopause sont des modulateurs importants de ce risque. L’objectif de cette étude était d’évaluer la contribution de l’adiponectine au profil de risque cardiométabolique de femmes porteuses de variants dans le gène LPL connus pour être associés avec la LPLD. L'échantillon étudié comprenait 568 femmes d'origine canadienne-française, dont 127 avec une LPLD et 441 non LPLD (contrôles). L'influence de l'adiponectine sur le risque associé à la LPLD a été évaluée en utilisant des analyses de régression multiples prenant en compte l’influence du statut ménopausique, des variables anthropométriques, du bilan lipidique, de la glycémie à jeun et du tabagisme. Les résultats montrent que les niveaux d'adiponectine étaient significativement plus faibles dans les groupes LPLD. La contribution des valeurs faibles d’adiponectine au profil de risque cardiométabolique des sujets LPLD était indépendante du statut ménopausique et de toutes les autres covariables étudiées. Cela suggère que l'adiponectine contribue au profil de risque cardiométabolique chez les femmes porteuses d’une mutation connue pour être associée avec la LPLD. / The cardiovascular risk significantly increases after menopause. Lipoprotein lipase (LPL) is a key enzyme in the metabolism of triglyceride (TG)-rich lipoproteins which contributes to cardiometabolic homeostasis. Adiponectin is an adipocytokine which also influences the cardiometabolic status. The objective of this study was to evaluate the contribution of plasma adiponectin to the cardiometabolic status of women carrying loss-of-function LPL gene variants (LPLD). A total of 568 French Canadian women (127 LPLD and 441 controls) were included. The association of plasma adiponectin with LPLD was assessed using multiple regression models. Cardiometabolic covariates included anthropometrics, lipids (TG, HDL-C, LDL-C, apo B), fasting glucose and smoking. Mean plasma adiponectin concentration was significantly lower in women with LPLD. Women carrying loss-of function LPL gene mutations also presented a significantly higher risk of coronary artery disease. In conclusion, these results suggest that low plasma adiponectin significantly contributes to the cardiometabolic risk profile of postmenopausal women carrying loss-of-function LPL gene mutations, independently of anthropometrics, lipids and other covariates.

Lipoprotein(a) (Lp(a)) consists of an LDL-like particle and the specific protein apo(a), which is very similar to plasminogen. Apo(a) contains repeated kringle structures and a serine protease domain, which cannot be activated by t-PA. Lp(a) is considered to be a predictor for atherosclerotic disease. It has been found incorporated in atherosclerotic plaques and inhibits in vitro fibrinolysis. Lp(a) was determined in 1527 randomly selected individuals participating in the Northern Sweden WHO-MONICA project. A weak but significant relation between Lp(a) and increasing age was found. Menopausal status was the strongest independent predictor of Lp(a) level in women. Fibrinogen was independently related to Lp(a) in both sexes. Only a minor fraction of Lp(a) variance could be explained for in a multiple regression model, which is in agreement with the contention that Lp(a) is highly genetically determined. Lp(a) was determined in 1571 patients investigated with coronary angiography because of suspected severe coronary artery disease (CAD). Patients with proven CAD at elective angiography had significantly higher Lp(a) than patients without significant CAD or healthy controls. Lp(a) was found to be an independent discriminator of CAD in both sexes. HLA-DR genotype 13 or 17 was found more frequently in 30 male patients with angiographic CAD at young age (&lt; 50 years) than in 30 age matched controls. These genotypes were common in patients with high Lp(a) levels, which indicates that Lp(a) may be related to immunological processes. The reaction of Lp(a) was investigated in 32 patients with acute myocardial infarction (AMI). Lp(a) increased during the first week, but the response was comparatively weak. Individual Lp(a) responses were heterogeneous and no correlations to infarct size or changes in the acute phase proteins were found. In a randomized cross-over study on 36 hypercholesterolaemic patients treated with simvastatin/placebo during 12+12 weeks Lp(a) did not change significantly, but patients with high Lp(a) levels at baseline tended to develop further increased Lp(a). To conclude, Lp(a) was found to be an independent predictor of angiographic CAD in both men and women. Lp(a) levels are primarily genetically determined and only a small fraction of Lp(a) variance could be explained by other factors in this study. Lp(a) may be related to HLA DR types and immunological processes involved in atherosclerotic disease. Lp(a) increased slightly during the first week of AMI, but was not related to changes in the acute-phase proteins. The effective LDL-lowering agent simvastatin did not influence Lp(a) significantly. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1993, härtill 5 uppsatser.</p> / digitalisering@umu

Individuals with high levels of plasma triglycerides are at high risk to develop cardiovascular disease (CVD), currently one of the major causes of death worldwide. Recent epidemiological studies show that loss-of-function mutations in the APOC3 gene lower plasma triglyceride levels and reduce the incidence of coronary artery disease. The APOC3 gene encodes for apolipoprotein (APO) C3, known as an inhibitor of lipoprotein lipase (LPL) activity. Similarly, a common gain-of-function mutation in the LPL gene is associated with reduced risk for CVD. LPL is central for the metabolism of lipids in blood. The enzyme acts at the endothelial surface of the capillary bed where it hydrolyzes triglycerides in circulating triglyceride-rich lipoproteins (TRLs) and thereby allows uptake of fatty acids in adjacent tissues. LPL activity has to be rapidly modulated to adapt to the metabolic demands of different tissues. The current view is that LPL is constitutively expressed and that the rapid modulation of the enzymatic activity occurs by some different controller proteins. Angiopoietin-like protein 4 (ANGPTL4) is one of the main candidates for control of LPL activity. ANGPTL4 causes irreversible inactivation through dissociation of the active LPL dimer to inactive monomers. Other proteins that have effects on LPL activity are the APOCs which are surface components of the substrate TRLs. APOC2 is a well-known LPL co-factor, whereas APOC1 and APOC3 independently inhibit LPL activity. Given the important role of LPL for triglyceride homeostasis in blood, the aim of this thesis was to find small molecules that could increase LPL activity and serve as lead compounds in future drug discovery efforts. Another aim was to investigate the molecular mechanisms for how APOC1 and APOC3 inhibit LPL activity. Using a small molecule screening library we have identified small molecules that can protect LPL from inactivation by ANGPTL4 during incubations in vitro. Following a structure-activity relationship study we have synthesized lead compounds that more efficiently protect LPL from inactivation by ANGPTL4 in vitro and also have dramatic triglyceride-lowering properties in vivo. In a separate study we show that low concentrations of fatty acids possess the ability to prevent inactivation of LPL by ANGPTL4 under in vitro conditions. With regard to APOC1 and APOC3 we demonstrate that when bound to TRLs, these apolipoproteins prevent binding of LPL to the lipid/water interface. This results in decreased lipolysis and in an increased susceptibility of LPL to inactivation by ANGPTL4. We demonstrate that hydrophobic amino acid residues that are centrally located in the APOC3 molecule are critical for attachment of this protein to lipid emulsion particles and consequently for inhibition of LPL activity. In summary, this work has identified a lead compound that protects LPL from inactivation by ANGPTL4 in vitro and lowers triglycerides in vivo. In addition, we propose a molecular mechanism for inhibition of LPL activity by APOC1 and APOC3.

Heat shock protein (HSP)27 is traditionally described as an intracellular chaperone and signaling molecule, but growing evidence suggests it is released from immune cells where it plays an anti-inflammatory role during atherogenesis. Previously, the O’Brien lab found that overexpression of HSP27 led to augmented HSP27 serum levels in female apolipoprotein E knockout (ApoE-/-) mice, attenuated atherogenesis, and inhibited macrophage foam cell formation via physical binding with scavenger receptor (SR)-A. However, the precise mechanism of atheroprotection remained elusive. This thesis sought to ascertain the mechanism(s) by which HSP27 prevents foam cell formation, and determine if SR-A, a key receptor involved in the uptake of lipid into macrophages, plays an important role in HSP27-mediated atheroprotection. Pre-treatment of human macrophages with recombinant HSP27 (rHSP27) inhibited acytelated low density lipoprotein (acLDL) binding and uptake independent from receptor competition effect. Reduction in uptake was associated with attenuation of expression of SR-A mRNA, total protein, and cell surface expression. To explore the signaling mechanism by which HSP27 modulated SR-A expression it was hypothesized that nuclear factor-kappa B (NF-kB), a major regulator of many atherosclerosis gene programs, is altered by extracellular HSP27. Indeed, rHSP27 markedly activated NF-kB signaling in macrophages. Using an inhibitor of NF-kBsignaling there was an attenuation of rHSP27-induced inhibition of SR-A gene and protein expression, as well as lipid uptake, suggesting that SR-A expression is regulated by NF-kB activation. Lastly, to investigate if SR-A is required for HSP27-mediated atheroprotection in vivo, ApoE-/- and ApoE-/-SR-A-/- mice fed a high fat diet were treated with rHSP25, the mouse orthologue of HSP27, or PBS for 3 weeks. While rHSP25 therapy equally reduced serum cholesterol levels in the mouse cohorts, aortic atherogenesis, assessed using en face and sinus cross-sectional analyses, was attenuated in ApoE-/- mice but not ApoE-/-SR-A-/- mice. In conclusion, rHSP27 inhibits foam cell formation by downregulating SR-A expression. This effect may be associated with NF-kB activation. Reductions in atherosclerotic burden by rHSP27 require SR-A, and are independent of changes in serum cholesterol levels, highlighting the importance of macrophage lipid uptake in atherogenesis. Results presented in this thesis demonstrate that SR-A is a major target for HSP27 atheroprotection in the vessel wall, and provide an impetus for further studies that investigate the potential therapeutic value of HSP27.

The consumption of high-fat hamburger enriched with saturated fatty acids (SFA) and trans-fatty acids (TFA) may increase risk factors for cardiovascular disease, whereas hamburger enriched with monounsaturated fatty acids (MUFA) may have the opposite effect. Ten mildly hypercholesterolemic men consumed five, 114-g hamburger patties per week for two consecutive phases. Participants consumed low-MUFA (high SFA) hamburger (MUFA:SFA = 0.95; produced from pasture-fed cattle) for 5 wk, consumed their habitual diets for 3 wk, and then consumed high-MUFA hamburger (MUFA:SFA = 1.31; produced from grain-fed cattle) for 5 wk. These MUFA:SFA were typical of ranges observed for retail ground beef. Relative to habitual levels and levels during the high-MUFA phase, the low-MUFA hamburger: increased plasma palmitic acid, palmitoleic acid, and triacylglycerols (P < 0.01); decreased HDL cholesterol (HDL-C) and LDL particle diameter percentile distributions (P < 0.05); and had no effect on LDL-C or plasma glucose (P > 0.10). Plasma palmitoleic acid was positively correlated with triacylglycerols (r = 0.90), VLDL-C (r = 0.73), and the LDL:HDL (r = 0.45), and was negatively correlated with plasma HDL-C (r = -0.58), whereas plasma palmitic, stearic, and oleic acid were negatively correlated with LDL particle diameter (all P <= 0.05). Because plasma palmitoleic acid was derived from [delta]9 desaturation of palmitic acid in the liver, we conclude that alterations in hepatic stearoyl-CoA desaturase activity may have been responsible for the variation in HDL-C and triacylglycerols caused by the low-MUFA and high-MUFA hamburgers. Cattle with a genetic predisposition to deposit MUFA in their lean and fat tissues, such as Wagyu cattle can be used to produce beef products that are especially enriched with oleic acid and lower in SFA and TFA, and feeding practices can further enhance the composition of beef fat. This indicates that ground beef or hamburger products can be produced that are naturally enriched with oleic acid, and conversely that certain production practices can impair the nutritional quality of beef fat. Finally, we cannot discern from this study design whether the high-MUFA hamburger reversed the effects of the low-MUFA hamburger, or whether the subjects gradually adapted to the elevated intake of total fat. It is clear, however, that the high-MUFA hamburger did not exacerbate any of the effects of the low-MUFA hamburger and can be viewed as at least neutral in its effects on HDL-C and triacylglycerols.

Introdução: A obesidade e uma doenca cronica, com determinantes geneticos, metabolicos e comportamentais, que se caracteriza pelo acumulo de adiposidade no organismo. Em paralelo, as modificacoes oxidativas da lipoproteina da baixa densidade (LDL) tambem estao aumentadas na obesidade, gerando LDL minimamente oxidada, tambem chamada de LDL eletronegativa (LDL-). Nesse contexto, os adolescentes, com sua intensa mudanca de habitos alimentares, comportamentos sociais e alteracoes anatomo-fisiologicas, compoem um grupo com risco de sobrepeso e obesidade aumentado. Objetivo: Avaliar a influencia do sobrepeso e da obesidade na geracao da lipoproteina de baixa densidade eletronegativa (LDL-) em adolescentes. Metodologia: Cento e cinquenta adolescentes com idade entre 10 e 15 anos, de ambos os sexos, foram avaliados quanto a antropometria (peso, altura, circunferencias de braco e cintura) e o habito alimentar (Questionario de Frequencia Alimentar). Avaliou-se ainda o conteudo de LDL- e seus auto-anticorpos, o perfil lipidico, marcadores inflamatorios (IL-6 e PCR) e antioxidantes plasmaticos (-tocoferol e retinol). Resultados: O perfil lipidico do grupo Obeso apresentou diferenca significativa em relacao aos Eutroficos observando maiores concentracoes para Colesterol total (p=0,007) e LDL-c (p=0,033) e menores concentracoes para HDL-c (p=0,001). O conteudo de colesterol associado a VLDL e os Triglicerideos foi semelhante entre grupos (p=0,126). Em relacao ao conteudo de LDL- no plasma, o grupo Eutrofico apresentou valores inferiores aos grupos Sobrepeso (p=0,021) e Obeso (p=0,015). Para as concentracoes de auto-anticorpos anti-LDL- nao houve diferenca significativa entre os grupos. Para a concentracao de IL-6 os 3 grupos apresentaram comportamento estatisticamente semelhante (p=0,678). De modo contrario, 11 a concentracao plasmatica de PCR nos grupos Sobrepeso e Obeso foi superior a observada no grupo Eutrofico (p<0,001). Avaliando os antioxidantes, a concentracao de -tocoferol no grupo Eutrofico apresentou valores superiores aos grupos Sobrepeso (p=0,012) e Obeso (p<0,001), sendo esses semelhantes entre si (p=0,798). A avaliacao dos habitos alimentares, atraves do QFA, o grupo Obeso apresentou consumo de energia, proteinas, carboidratos, vitaminas A, E e C e fibras superior ao grupo Eutrofico (p= 0,016, p= 0,045, p = 0,004, p=0,044, p=0,028, p=0,017 e p=0,024 respectivamente). Apos o ajuste pela energia, somente proteinas (p=0,002) e retinol (p=0,049) apresentaram valores diferentes entre os grupos. Conclusões: Os resultados obtidos mostraram que adolescentes obesos e com sobrepeso apresentam perfil metabolico e oxidativo alterado em relacao aos adolescentes eutroficos. Portanto, o monitoramento de variaveis bioquimicas em adolescentes, torna-se importante para o diagnostico precoce de obesidade e doencas associadas. / Introduction: Some evidence suggests that the prevalence of overweight and obesity has significantly increased in the pediatric population. Obesity represents a chronic and inflammatory disease, where oxidative modification is associated. Many factors modulate the oxidative susceptibility of LDL and produces the LDL- and diet is considered very important in this process. Subnormal antioxidant levels may contribute to the increased risk of atherosclerosis in obese subjects. Objective: to evaluate the influence of overweight and obesity on eletronegative low density lipoprotein (LDL-) in adolescents. Methodology: The sample was composed for 150 adolescents, with 10 to 15 years old, both gender. They were evaluated by anthropometric profile and habitual food consumption. After 12 hour of fat, a blood sample was collected, and from the serum, was analyzed the serum lipids, LDL- and you respective antibodies, inflammatory profile (PCR and IL-6) and the alfa-tocopherol and retinol concentrations. Results: The serum lipids had a significant difference between Eutrophic and Obese group for of total- cholesterol (p=0,007), HDL-c (p=0,001) and LDL-c (p=0,033), but for VLDL-c and TG they were similar (p=0,126). On the content of LDL- in plasma, in Eutrophic group had lower values than Overweight (p=0,021) and Obeso groups (p=0015). For the concentrations of Auto-antibodies anti-LDL- there was no significant difference between groups. For the concentration of IL-6 the 3 groups had statistically similar behavior (p=0678). In contrary, the plasma concentration of CRP in Overweight and Obese groups was higher than Eutrophic group (p<0001). Judging from the antioxidants, the concentration of alfa-tocopherol in the Eutrophic group showed values greater than Overweight (p=0012) and Obese groups (p<0001), wich are similar to each other (p=0798). The assessment of habitual food consumption, through the FFQ, the Obese group presented consumption of energy, protein, carbohydrate, vitamins A, E and C and fiber above the group Eutrophic (p=0016, p=0045, p=0004, p=0028, p=0017, respectively). After adjusting for energy, only protein (p=0002) and retinol (p=0049) had different values between the groups. Conclusions: The present study shows that overweight and obese adolescents showed a metabolic and oxidative profile worse than eutrophic adolescents. Therefore, the monitoring of clinical and biochemical variables in adolescents, it is important for early diagnosis of obesity and related diseases.

A aterosclerose, doença sistêmica caracterizada pelo acúmulo de lipídios e elementos fibrosos nas artérias, é uma das principais causas de morte em diversos países. Partículas de lipoproteínas de baixa densidade (LDL) oxidadas estão presentes nas lesões aterogênicas, evidenciando a correlação entre estas partículas e a doença aterosclerótica. Este trabalho apresenta estudos de caracterização óptica e estrutural de lipoproteínas humanas nativas e oxidadas in vitro. As caracterizações foram realizadas por meio de diversas técnicas, sendo as principais a Varredura-Z e o espalhamento de raios X a baixos ângulos (SAXS) . Nos estudos de caracterização óptica verificou-se que a resposta não-linear das amostras de LDL está relacionada tanto com o seu conteúdo de antioxidantes, quanto com sua concentração de hidroperóxidos. Com relação à caracterização estrutural, foi proposto um novo método de análise para os dados de SAXS. Neste método, que mostrou-se mais adequando frente àqueles existentes na literatura, a curva de contraste de densidade eletrônica é obtida diretamente da curva de intensidade de espalhamento. Por meio das análises realizadas concluímos que as partículas de LDL apresentam pequenas alterações estruturais apenas quando comparamos a amostra nativa com aquela oxidada por 18 horas. São apresentados ainda alguns resultados exploratórios obtidos, tanto na caracterização óptica quanto na estrutural, para as lipoproteínas de alta densidade (HDL), que apontam para uma maior resistência deste tipo de lipoproteína ao processo oxidação. Por fim, é possível afirmar que a técnica de Varredura-Z é sensível a mudanças que ocorrem no início do processo oxidativo das lipoproteínas, enquanto a técnica de SAXS é sensível a mudanças em estágios mais avançados do mesmo processo. / Atherosclerosis, which is a systemic disease characterized by the accumulation of lipids and fibrous elements in the arteries, is a major cause of death in many countries. Particles of oxidized low density lipoproteins (LDL) are present in atherogenic lesions, showing the correlation between these particles and atherosclerosis. This thesis presents studies of structural and optical characterization of native and in vitro oxidized human lipoproteins. Characterizations were carried out by means of various techniques, the main ones being Z-scan (ZS) and small angle X-ray scattering (SAXS). In the optical characterization studies it was found that the non-linear response of LDL samples is associated with their antioxidant contents and with their concentration of hydroperoxides. With respect to the structural characterization, we propose a new method of analysis for the SAXS data. In this method, which is more suitable than those existing in the literature, the electron density curve is obtained directly from the scattering intensity curve. Through these analyses we conclude that LDL particles exhibit only small structural changes when native LDL sample is compared to the $18$ hours oxidized one. We also present preliminary results, both in structure and in optical characterization, for the high density lipoprotein (HDL), which presents a greater resistance (comparing to LDL) to the oxidation process. Finally, it is possible to say that the ZS technique is sensitive to changes that occur in early stages of the lipoprotein\'s oxidative process, while the SAXS technique is sensitive to changes in the later stages of the same process.

7-cetocoleterol (7KC) é um oxisterol conhecido por inibir a proliferação celular e por ser citotóxico. Desenvolvemos uma nanoemulsão contendo 7KC (LDE/7KC) que demonstrou efeito anti-proliferativo sobre as linhagens RPMI 8226 (mieloma) e melanoma (B16F10), in vitro, sendo preferencialmente captada via receptores de LDL. No presente trabalho avaliamos, in vivo, a cinética plasmática, biodistribuição, ação anti-tumoral e parâmetros tóxico-hematológicos em camundongos portadores de melanoma. A cinética plasmática apresentou um decaimento estatisticamente igual entre os animais portadores de melanoma e não portadores. Em relação à biodistribuição da nanoemulsão, houve um acúmulo de seus componentes radioativamente marcados, principalmente no fígado e no tumor, sugerindo sua captação via receptores de LDL. LDE/7KC promoveu uma redução superior a cinqüenta por cento do tamanho do tumor, que apresentou maior área de necrose e menor quantidade de vasos. Nos camundongos tratados com LDE/7KC houve um aumento da sobrevida. As análises toxico-hematológicas demonstraram que a nanoemulsão apresentou pouca ou nenhuma toxicidade. Os resultados demonstram a possibilidade da utilização da nanoemulsão LDE/7KC como um agente no tratamento do câncer, com poucos efeitos colaterais, devido a sua seletividade aos receptores da LDL. / 7-ketocholesterol (7KC) is an oxysterol known to inhibit cell proliferation and to be cytotoxic. A nanoemulsion containing-7KC (LDE/7KC) was shown to have antiproliferative effects on RPMI 8226 myeloma cell line and melanoma (B16F10), in vitro. This particle is taken up mainly by LDL receptors. Here we have evaluated the plasma kinetic, biodistribution, anti-tumoral action and hematologic toxicity of LDE/7KC in melanoma bearing mice. The nanoemulsion accumulated in the liver and tumor, tissues with a high expression of LDL receptors. LDE/7KC promoted a tumor size reduction over fifty percent. An increased necrosis area and a decreased amount of blood vessels were found. An increased survival rate was observed. The hematolgic analyses demonstrated a lack of toxicicity. The results shows the possibility to use the LDE/7KC nanoemulsion as an agent for cancer treatment, with few collateral effects probably due to its internalization by LDL receptors.

Resultados obtidos anteriormente pelo nosso grupo mostraram que a proteína de fase aguda amilóide sérica A (SAA) é um potente estímulo para a expressão de mRNA e liberação de TNF-&#945;, IL-1-&#946; e IL-8 em leucócitos humanos, além de atuar como priming para a liberação de espécies reativas de oxigênio (EROs) por neutrófilos. Nosso objetivo, nesse trabalho, foi mostrar a presença de SAA em exsudatos e definir sua origem, além de verificar sua atividade pró-inflamatória in vivo. Para tanto, utilizamos soro e exsudatos pleurais de 32 pacientes com pneumonia. Mostramos primeíramente a presença da SAA no material inflamatório através de SDS-PAGE, immunoblotting e HPLC. A quantificação de SAA nas amostras foi realizada por ELISA. Nestas amostras também foram determinadas as concentrações de proteína total, proteína C reativa (PCR), apo A-I, apo A-II, apo B, colesterol total, triglicérides, TNF-&#945;, IL-1-&#946; e IL-8. A análise integrada dos nossos resultados indica que há uma passagem preferencial da HDL para o foco inflamatório, quando comparada as demais lipoproteínas. A SAA presente em exsudatos é originada do soro e deve sofrer intensa degradação ou associação com células. O efeito da SAA no exsudato é pró-inflamatório, sendo que esta proteína poderia ser um dos alvos para as enzimas proteolíticas e EROs presentes em exsudatos. Acreditamos que este trabalho contribua significamente para a compreensão do, ainda incerto, papel da SAA no processo inflamatório e dá nova abrangência para as funções da HDL e sua participação na reposta imune. / Previous results from our lab showed that the acute phase protein serum amyloid A (SAA) is a potent stimulus for the expression of mRNA and secretion of TNF-&#945;, IL-1-&#946; and IL-8 from human leukocytes. Furthermore SAA primes neutrophils for the generation of reactive oxygen species (ROS). Our goal here was to show the presence of SAA in exudates and define its origin, besides the verification of its proinflammatory activity in vivo. To achieve this goal we used serum and pleural exudates from 32 patients with pneumonia. At first, we showed the presence of SAA in the exudate through SDS-PAGE, immunoblotting and HPLC. SAA was quantified by ELISA. Besides SAA, we also determined the concentrations of total protein, C reactive protein, apo A-I, apo A-II, apo B, cholesterol, triglyceride, TNF-&#945;, IL-1-&#946; e IL-8. The integrate analysis of our results indicates that there is a preferential leakage of HDL to the inflammatory focus when compared to other lipoproteins. SAA present in exudates is originated from serum and may be intensively degraded or associated to cells. The effect of SAA in the exudate is proinflammatory and this protein may be a target for proteolytic enzymes and for ROS present in exudates. We believed that this work adds new insights to the, yet undefined, role of SAA in the inflammatory process and gives a broader compreension to the functions of HDL and its participation in the on the immune response.

Introdução - A dieta cetogênica (DC) é um tratamento não farmacológico prescrito especialmente para crianças e adolescentes com epilepsia refratária. Objetivo - Avaliar o impacto da dieta cetogênica clássica nas características oxidativas, físicas e lipídicas das lipoproteínas de crianças e adolescentes com epilepsia refratária. Métodos - Ensaio clínico não controlado de séries temporais com recrutamento de crianças e adolescentes com epilepsia refratária de 1 a 19 anos de ambos os sexos do Instituto da Criança do Hospital das Clínicas da FMUSP. Parâmetros bioquímicos foram analisados: perfil lipídico, concentração de ácidos graxos não esterificados (AGNEs), LDL eletronegativa [LDL(-)], Anticorpo anti- LDL(-), substâncias reativas ao ácido tiobarbitúrico (TBARs), subfrações da lipoproteína de alta densidade (HDL) e lipoproteína de baixa densidade (LDL). Além das análises bioquímicas foram avaliadas medidas antropométricas para classificação do estado nutricional, medidas de composição corporal por bioimpedância elétrica e consumo alimentar por registro alimentar de 3 dias. Todas essas medidas foram coletadas antes da DC (T=0), 3 meses após a DC (T1) e 6 meses após a DC (T2). Resultados - A concentração de colesterol total (CT), triacilgliceróis (TG), LDL, HDL, apolipoproteínas (APO A-I e APOB) e não-HDL aumentaram significativamente nos momentos T1 e T2. As razões CT/HDL, LDL/HDL e APOB/APOA-I também apresentaram aumento significativo indicando aumento superior das lipoproteínas e apolipoproteínas mais aterogênicas. Apesar desses aumentos, nenhuma dessas relações ou concentração de lipoproteínas e apolipoproteínas apresentaram aumento progressivo comparando-se T1 versus T2. De modo contrário, observamos aumento progressivo ao longo do tempo na concentração de AGNEs, partículas pequenas de LDL e redução no tamanho médio da LDL de 27,3 nm no T0 versus 26,7 nm no T2. A concentração de TBARs aumentou enquanto a LDL(-) reduziu. A classificação do estado nutricional bem como o % de massa magra e % de massa gorda não mudaram ao longo do tempo. Conclusões - A DC apresentou impacto negativo no metabolismo lipídico contribuindo com o aumento de partículas pequenas de LDL e um fenótipo mais aterogênico. / Introduction - The ketogenic diet (KD) is a non-pharmacological treatment prescribed for children and adolescents with refractory epilepsy. Objective To assess the impact of the classic ketogenic diet in the oxidative, physical and lipid lipoprotein characteristics of children and adolescents with refractory epilepsy. Methods - Single arm, times series trial with recruitment of children and adolescents 1-19 years of both sexes of the Instituto da Criança do Hospital das Clínicas da FMUSP, after doctor indication for treatment with KD. Biochemical parameters were analyzed: lipid profile, level of non esterified fatty acids (NEFAS), LDL electronegative [LDL (-)], anti-LDL (-), thiobarbituric acid reactive substances (TBARS), subfractions of high density lipoprotein (HDL), subfractions of low density lipoprotein (LDL) and LDL size. In addition, anthropometric measurements for classification of nutritional status, body composition by bioimpedance electrical and dietary intake through food records evaluated in 3 days. All these measures were collected before the KD (T = 0), three months after the KD (T1) and 6 months after KD (T2). Results - The level of total cholesterol (TC), triglycerides (TG), LDL, HDL, apolipoproteins (Apo A-I and Apo B) and non-HDL increased significantly in T1 and T2. The rations TC/HDL, LDL/HDL and APOB/APO A-I also showed a significant increase indicating higher increase in lipoproteins and apolipoproteins atherogenic. Despite these increases, any such rations or levels of lipoproteins and apolipoproteins progressive increase comparing T1 versus T2. Conversely, we observed a progressive increase along time in the levels of NEFAS, small LDL and reduction of LDL size of 27.3 nm (T0) to 26.7 nm (T2). The levels of TBARS increased while LDL (-) reduced. The classification of nutritional status as well as the % of lean mass and % of fat mass didn´t change along time. Conclusions - The KD showed a negative impact on lipid metabolism contributing to increased small LDL particles and a more atherogenic phenotype.