From animal experimentation, and studies using in vitro models, there was evidence in the literature to suggest that dietary fibre may influence contractility and motility of the gastrointestinal tract and long chain (LC) n-3 polyunsaturated fatty acids (PUFAs) from marine sources may influence contractility of smooth muscle cells in blood vessels. The hypothesis of this thesis was that dietary fish oil and/or fibre influence the contractility of isolated intact sections of gut smooth muscle tissue from small animal models. Methodology was established to measure in vitro contractility of intact pieces of guinea pig ileum with the serosal side isolated from the lumen. It was demonstrated that four amino acid peptides from κ-casein (casoxins) applied to the lumen overcame morphine-induced inhibition of contraction. Using this established technology, the guinea pig was used to investigate the effects of dietary fibre and fish oil supplementation on gut in vitro contractility. In separate experiments, changes in sensitivity to electrically-driven and 8-iso-prostanglandin (PG)E₂-induced contractility were demonstrated for dietary fibre and fish oil. A modified, isolated gut super-perfusion system was then established for the rat to validate these findings. It was subsequently shown that LC n-3 PUFA from dietary fish oil significantly increased maximal contraction in response to the G-protein coupled receptor modulators, acetylcholine and the eicosanoids PGE₂, PGF₂α, 8-iso-PGE₂ and U-46619 in ileum but not colon, without changes in sensitivity (EC₅₀), when n-3 PUFA as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) had been incorporated to a similar degree into the gut total phospholipid membrane pool. It was further established that the spontaneously hypertensive rat (SHR) had a depressed prostanoid (PGE₂and PGF₂α) response in the gut that could be restored by dietary fish oil supplementation (5% w/w of total diet) in the ileum but not the colon. Importantly, the muscarinic response in the colon of the SHR was increased by fish oil supplementation with DHA likely to be the active agent. Dietary fish oil dose experiments deduced differential increases in response occurred at fish oil concentrations of 1% for muscarinic and 2.5% (w/w) for prostanoid stimulators of the ileum with no difference in receptor-independent KCl-induced depolarization-driven contractility. Studies combining high amylose resistant starch (HAMS, 10% w/w) and fish oil (10% w/w) fed to young rats demonstrated a low prostanoid response that was enhanced by dietary fish oil but not resistant starch. There was however, an interactive effect of the HAMS and fish oil noted for the muscarinic-mimetic, carbachol. Generally, resistant starch increased the large bowel short chain fatty acid pool with a subsequent lower pH. Binding studies determined that while the total muscarinic receptor binding properties of an isolated ileal membrane fraction were not affected in mature rats by dietary fish oil, young rats had a different order of muscarinic receptor subtype response with a rank order potency of M₃ > M₁ > M₂ compared to mature animals of M₃ > M₂ > M₁ with fish oil altering the sensitivity of the M₁ receptor subtype in isolated carbachol-precontracted ileal tissue. In conclusion, experiments using the guinea pig and rat gut models demonstrated that dietary fish oil supplementation, and to a lesser degree fibre, increased receptor-driven contractility in normal and compromised SHR ileum and colon. Further, changes in responsiveness were demonstrated in the developing rat gut prostanoid and muscarinic receptor populations that could be altered by dietary fish oil. Preliminary evidence suggested that fish oil as DHA may alter receptor-driven gut contractility by mechanisms involving smooth muscle calcium modulation. Defining the role that dietary fibre and fish oil, and other nutrients, play in normal and diseased states of bowel health such as inflammatory bowel disease (IBD), where contractility is compromised, are among the ongoing challenges. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1316907 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2008

Thesis (Ph.D.)--Flinders University, School of Medicine, Dept. of Gastroenterology. / Typescript bound. Includes bibliographical references: (leaves 215-233) Also available in an electronic version via the Web.

Foram utilizadas 168 galinhas poedeiras Hisex White em delineamento experimental inteiramente casualizado, com duração de cinco semanas. As aves foram distribuídas em sete tratamentos com três repetições cada, com o objetivo de verificar a influência da suplementação de três fontes marinhas de PUFAs n-3 - óleos de salmão (SA) e de atum e sardinha (A/S) e mistura de algas marinhas (AL), bem como sua combinações (SA+A/S, AL+SA, AL+A/S) - em relação ao grupo controle alimentado com ração basal de milho e soja (CON), sobre a qualidade do ovo e a composição lipídica da gema. A qualidade externa e interna do ovo não foi alterada significativamente pela adição de fontes de PUFAs n-3 na dieta das aves. A relação entre os lípides saturados : monoinsturados : poliinsaturados da gema (3,5 : 4,5 : 2,0) manteve-se constante com a adição dos suplementos de PUFAs n-3 na ração. Os óleos de salmão (SA) e de atum e sardinha (A/S) revelaram-se mais efetivos no enriquecimento da gema do ovo em PUFAs n-3, em especial o DHA. A relação PUFAs n-6/ PUFAs n-3 sofreu redução significativa com a adição das fontes marinhas de ômega-3 à dieta das galinhas. O EPA, embora em teores mais baixos que o DHA na gema do ovo, apresentou incremento significativo com o uso dos óleos de peixes (SA e A/S) adicionado à dieta em relação ao CON. O consumo de dois ovos enriquecidos com DHA do presente estudo, por dia, provavelmente atenderia os requerimentos diários deste PUFA n-3 para o ser humano / To investigate the influence of three PUFAs n-3 marine sources - salmon oil (SA), tuna and sardine oil (A/S), marine algae (AL) and combinations (SA+A/S, AL+SA, AL+A/S) - on egg quality and egg lipid composition, compared to a corn/soy control group (CON), 168 Hisex White laying hens were assigned into seven treatments with three repetitions in a randomized design during a experimental period of five weeks. The external and internal egg quality were not significantly affected by the addition of PUFAs n-3 marine sources into the hen diets. The saturated : monounsaturated : polyunsaturated ratio (3.5:4.5:2.0) remained constant by the supplementation of the marine sources into the diets. The salmon oil and the tuna and sardine oil showed the best results of PUFAs n-3 egg yolk enrichment, mainly the DHA. The PUFAs n-6/PUFAs n-3 ratio was significantly reduced by the inclusion of PUFAs n-3 sources into the hen diets. The EPA, although with lower levels than DHA into the egg yolk, showed a significant increase by the use of salmon oil and tuna and sardine oil added to the diet as compared to the control group (CON). The consumption of two DHA enriched eggs from this study per day probably would reach the daily requirements of this PUFA n-3 for the human been

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Thesis (PhD) -- tellenbosch University, 2014. / ENGLISH ABSTRACT: This study is part of the continuing global research effort dedicated to finding alternative aquafeed ingredients, which not only replace fish meal and fish oil as sources of essential nutrients in aquafeeds, but also provide specialist functional properties when included in feeds. Due to constraints in supply of fish meal and fish oil originating from wild capture fisheries, the continually growing aquafeed industry requires new sources of raw materials for the production of high quality feeds. The aim of the study was to investigate the specialist functional properties of feed ingredients (with emphasis on immune-stimulation potential) derived from fish processing waste after enzymatic hydrolysis by endogenous proteolytic enzymes (autolysis). Further aims were to (i) quantify effects of these feed ingredients on production performance of two species relevant to the South African aquaculture industry, namely Mozambique tilapia Oreochromis mossambicus and South African abalone Haliotis midae, (ii) compare performance to commercially available enzymatically produced feed ingredients, and (iii) separate the functional effects of these fish processing waste derived feed ingredients from the acid used to preserve them against bacterial spoilage during the autolysis process. Oil recovered after autolysis of rainbow trout viscera proved to be an attractive feed ingredient due to favourable effects on the non-specific cellular immune function of both Mozambique tilapia and South African abalone. However, in South African abalone, increased immune function due to inclusion of fish oil was accompanied by a significant decrease in production performance. The inclusion of hydrolysed proteins, obtained by autolysis of fish waste, in aquaculture feeds also improved non-specific immunity and survival of Mozambique tilapia significantly – independently of the preserving acid – although the same was not observed for South African abalone. Production performance was dependent on dietary hydrolysed protein inclusion levels in both species; excessive inclusion resulted in decreased production performance. The performance of dietary hydrolysed protein from autolysis and those from commercial production processes were significantly different, possibly as a result of different raw material origins and production processes. It is further shown that formic acid can contribute to improved water stability in abalone feeds, a novel mode of action not previously described. The study concludes that the simple autolysis process for processing of fish waste can provide aquafeed ingredients with immune stimulatory potential, which can contribute to improved production performance in the Mozambique tilapia and the South African abalone. The result can contribute to improved sustainability of the aquafeed industry, through substitution of fish meal and fish oil derived from capture fisheries with processed fish waste components. / AFRIKAANSE OPSOMMING: Hierdie studie vorm deel van die voortdurende en wêreldwye soeke na nuwe akwakultuur voerbestanddele wat nie net vismeel en –olie kan vervang as bron van noodsaaklike voedingstowwe nie, maar wat ook gespesialiseerde funksionele eienskappe openbaar wanneer dit in akwavoere ingesluit word. As gevolg van beperkings in die voorsiening van vismeel en –olie afkomstig vanaf wilde visserye, word die voortdurend groeiende akwavoer bedryf genoodsaak om nuwe grondstowwe te benut vir die vervaardiging van hoë kwaliteit voere. Die doelwit van die studie was om moontlike gespesialiseerde funksionele eienskappe (met spesifieke klem op potensiële immuun-stimulasie) van voerbestanddele te ondersoek wat herwin is vanaf reënboogforel proseseringsafval, na ensiematiese hidrolise d.m.v. endogene ensieme teenwoordig in die afval (outolise). Verdere doelwitte was om (i) effekte op produksie prestasie van hierdie bestanddele te kwantifiseer in twee akwakultuur spesies relevant tot die Suid- Afrikaanse bedryf (naamlik die Mosambiekse kurper Oreochromis mossambicus en die Suid- Afrikaanse perlemoen Haliotis midae), (ii) om produksie prestasie te vergelyk met kommersieel beskikbare voerbestanddele voorberei d.m.v. ensiemtegnologie, en (iii) om die moontlike effekte van die voerbestanddele te skei van die van die sure gebruik om die bestanddele te preserveer tydens die outolitiese proses. Daar is bevind dat olie herwin na outolise van reënboogforel ingewande ‘n goeie voerbestanddeel is wat gunstige effekte op die nie-spesifieke, sellulêre immuniteit van beide Mosambiekse kurper en Suid-Afrikaanse perlemoen gehad het. In die Suid-Afrikaanse perlemoen het verbeterde immuunfunksie gepaard gegaan met ‘n verswakking in produksie prestasie. Die gehidroliseerde proteïen komponent van ge-outoliseerde prosesseringsafval het ook beduidende verbetering in nie spesifieke immuniteit en oorlewing van Mosambiekse kurper tot gevolg gehad - onafhanklik van die preserverende suur - maar dieselfde is nie in die Suid-Afrikaanse perlemoen waargeneem nie. Produksie prestasie was afhanklik van die insluitingsvlakke van gehidroliseerde proteïen in beide spesies en dit is bevind dat oormatige insluiting produksie nadelig beïnvloed. Prestasie van proteïen afkomstig van outolise en die van ‘n kommersiële produksieproses het beduidend verskil, moontlik as gevolg van verskillende grondstowwe en prosesseringstegnieke. Daar is verder vir die eerste keer getoon dat mieresuur ‘n beduidende verbetering in waterstabiliteit in sekere perlemoenvoere teweeg kan bring. Die studie kom tot die slotsom dat die eenvoudige outolise proses funksionele akwavoerbestanddele kan produseer wat kan bydra tot ‘n verbetering in produksie prestasie in die Mosambiekse kurper en Suid-Afrikaanse perlemoen. Die resultaat kan bydra tot verbeterde volhoubaarheid van die akwavoer bedryf, deur vismeel en –olie afkomstig van wilde visserye, te vervang.

Propriedades biológicas de ácidos graxos poli-insaturados ômega-3 (AGPIs ômega-3), particularmente dos ácidos eicosapentaenoico (EPA) e docosahexanoico (DHA), sugerem seu benefício clínica em condições inflamatórias. A incorporação leucocitária de AGPIs ômega-3 é importante para que suas propriedades anti-inflamatórias ocorram. Comparado com administração por via digestiva, a infusão parenteral de emulsões lipídicas (EL) contendo AGPIs ômega-3 tem incorporação celular precoce. Experimentalmente, em ratos saudáveis, o pico de incorporação celular de AGPIs ômega-3 ocorreu 72 horas após a infusão parenteral de ELs contendo óleo de peixe como fonte de EPA e DHA. Em ratos a incorporação celular de AGPIs ômega-3 administrados por via parenteral foi mais rápida quando infundidos em conjunto com triglicérides de cadeia média (TCM) do que associados a AGPIs. Uma EL parenteral contendo quantidades elevadas de TCM (50%) em sua formulação tornou-se recentemente disponível para a prática clínica e poderia ser útil para facilitar a incorporação celular de AGPIs ômega-3. Nosso trabalho avaliou experimentalmente as modificações de incorporação leucocitária de AGPIs ômega-3 após infusão parenteral de nova EL contendo óleo de peixe e alto teor de TCM (grupo TCM / TCL / OP). Estudamos estas modificações em células mononucleares e polimorfonucleares após 48 e 72 horas de infusão e em comparação com EL experimental contendo a mesma quantidade de AGPIs ômega-3 e menor de TCM (grupo TCL / OP). Os resultados demonstraram que, após 48 h de infusão, o grupo OP apresentou menos ômega-6 do que o grupo TCM, enquanto as quantidades de ômega 3 eram similares tanto em células mono, quanto em polimorfonucleares. Após 72h, todos os grupos apresentaram diminuição no conteúdo de AGPIs ômega-6 e ômega-3. A razão entre ômega-6 / ômega-3 foi similar entre os grupos no tempo 48h e melhor no grupo OP no tempo 72h. Nossos resultados indicam que a presença de TCM na EL parenteral contendo OP parece não influenciar a dinâmica de incorporação leucocitária de AGPIs / Biological properties of omega-3 polyunsaturated fatty acids (omega-3 PUFA), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), suggest its clinical benefit under inflammatory conditions. The leukocyte incorporation of omega-3PUFAs is important for its anti-inflammatory properties to occur. Compared with digestive administration, parenteral infusion of lipid emulsions (LE) containing omega-3 PUFAs has early cellular uptake. Experimentally, in healthy rats, the peak cellular uptake of omega-3 PUFAs occurred 72 hours after parenteral infusion of fish oil lipid emulsion (FOLE) as the source of EPA and DHA. In rats, the cellular uptake of parenterally administered omega-3 PUFAs was faster when infused together with medium chain triglycerides (MCT). A parenteral LE containing high amounts of MCT (50%) in its formulation become available for clinical practice and could be useful to facilitate the cellular uptake of omega-3 PUFAs. Our work experimentally evaluated the leukocyte incorporation modifications of omega-3 PUFAs after parenteral infusion of new FOLE and high MCT content (MCT / LCT / FO group). We studied these changes in mononuclear and polymorphonuclear leuckocytes after 48 and 72 hours of infusion and compared with experimental LE containing the same amount of omega-3 and lower MCT-PUFAs (LCT / FO group). The results showed that, after 48 h of infusion, the FO group had less omega-6 than the MCT group, whereas the omega 3 amounts were similar in both mono- and polymorphonuclear cells. After 72 h, all groups had a decrease in the content of PUFAs omega-6 and omega-3. The ratio of omega-6 / omega-3 was similar between the groups at time 48h and better in the FO group at time 72h. Our results indicate that the presence of MCT in FOLE does not seem to influence the leukocyte incorporation dynamics of omega-3 PUFAs

Introdução: A infusão parenteral de emulsão lipídica (EL) de óleo de peixe (OP), rica em ácidos graxos ômega-3 (AG n-3), está associada à diminuição do perfil de mediadores pró-inflamatórios em estudos experimentais e clínicos. AG n-3 se incorporam em poucas horas em membranas celulares e geralmente são administrados após a agressão inflamatória. A pancreatite aguda (PA) experimental é modelo de inflamação, local e sistêmico, bem estabelecido. Objetivo: O presente estudo avaliou o efeito da infusão parenteral de EL de OP por curto período, antes da indução de PA, sobre a modulação da resposta inflamatória sistêmica e sobrevida. Métodos: Após cateterização do sistema venoso central, ratos isogênicos Lewis receberam infusão parenteral de EL de óleo de peixe ou solução salina durante 48 horas, quando então foram submetidos à pancreatite aguda, pela injeção retrógrada de 0,5 mL de solução de taurocolato de sódio a 3% no duto pancreático. Após indução de PA, nos períodos de 2, 12 e 24 horas, os animais foram sacrificados para coleta de amostras de sangue e de tecidos para dosagem de marcadores inflamatórios e histopatológicos. Paralelamente, 20 animais de cada grupo foram observados até sete dias após indução de PA, para avaliação de sobrevida. Resultados: O tratamento com EL de óleo de peixe foi associado com diminuição de citocinas pró-inflamatórias IL-1beta (p=0,0006) e IL-6 (p=0,05), diminuição de IL-4 (p= 0,0019) e tendência no aumento de anti-inflamatória IL-10 (p= 0,06), após 24 horas de PA; e com aumento da expressão pulmonar e hepática de proteínas de choque térmico HSP 90, 2 e 12 horas após PA, respectivamente. Após infusão de EL de óleo de peixe, não foram encontrados efeitos sobre os níveis de malonaldeído no fígado e na histopatologia do pâncreas, no período de 2 e 12 horas pós pancreatite aguda; e na taxa de sobrevida, em relação aos demais grupos (p > 0,05). Conclusão: Nossos resultados sugerem que a infusão parenteral de EL de OP 48 horas antes da indução de pancreatite aguda experimental parece influenciar favoravelmente a produção de citocinas inflamatórias e HSP90 hepática e pulmonar, sem impactar sobre a histopatologia da lesão pancreática e a taxa de sobrevida / The parenteral infusion of fish oil (FO) lipid emulsion (LE), rich in omega-3 fatty acids (n-3 FA), is associated with the decrease of pro-inflammatory mediators profile in experimental and clinical studies. N-3 FA are incorporated in a few hours in cell membranes and are generally administered after the inflammatory injury. The experimental acute pancreatitis (AP) is an inflammation, local and systemic well-established model. This study evaluated the effect of parenteral infusion of fish oil LE for a short period before AP induction, on the modulation of systemic inflammatory response and survival. For this, after the central venous catheterization Lewis rats received parenteral infusion of fish oil LE or saline solution for 48 hours, when they were induced to acute pancreatitis by retrograde injection of 0.5 mL of sodium taurocholate at 3% in pancreatic duct. After AP induction, in periods of two, 12 and 24 hours, the animals were sacrificed to collect blood samples and tissues for measurement of inflammatory markers and histopathological. In parallel, 20 animals in each group were observed up to 7 days after induction of AP, for survival analysis. The treatment with fish oil LE was associated with decreased of pro-inflammatory cytokines IL-1beta (p = 0.0006) and IL-6 (p = 0.05), reduction of IL-4 (p = 0.0019) and upward trend of anti-inflammatory IL-10 (p = 0.06) after 24 hours of AP; and increased pulmonary and hepatic expression of heat shock proteins HSP 90 two and 12 hours after AP, respectively. After infusion of fish oil LE, there were no effects on malondialdehyde levels in the liver and the pancreas histopathology in the periods of 2 and 12 hours after acute pancreatitis; and survival rate, compared to the other groups (p > 0.05). Our results suggest that parenteral infusion of FOLE 48 hours before the induction of experimental acute pancreatitis appears to favorably influence the production of inflammatory cytokines; hepatic and pulmonary HSP90, without impacting on the histopathology of pancreatic injury and the survival rate

INTRODUÇÃO: Emulsões lipídicas parenterais (EL) contendo óleo de peixe podem modular favoravelmente a resposta inflamatória e manter ou promover a resposta imunológica, mas há dados insuficientes sobre seu impacto em funções de células da imunidade inata. OBJETIVO: Verificar o efeito da administração endovenosa de EL composta por mistura de triglicérides de cadeia média e óleos de soja, oliva e peixe sobre a migração e fagocitose de leucócitos de ratos, em comparação à EL composta por mistura física de triglicérides de cadeia média e cadeia longa - TCM/TCL, suplementada ou não com óleo de peixe (OP). MÉTODOS: Ratos (Lewis) isogênicos (n=40) foram submetidos à cateterização da veia jugular externa para acesso parenteral. Os animais foram randomizados em quatro grupos, de acordo com sua infusão endovenosa: grupo SMOF: EL contendo 30% de óleo de soja (TCL), 30% de TCM, 25% de óleo de oliva e 15% de OP; grupo TCM/TCL: EL contendo TCM e TCL (1:1 v/v); grupo TCM/TCL/OP: EL composta por TCM/TCL com adição de OP (8:2 v/v); grupo SF: solução fisiológica. Um grupo de animais sem cateterismo venoso também foi desenvolvido (CO-NC). No quinto dia de experimento e após injeção de carvão coloidal pela veia caudal, amostras de sangue e tecido (fígado, pulmão e baço) foram coletadas para análise quimiotática de neutrófilos (câmara de Boyden adaptada) e quantificação do número de macrófagos fagocitantes do carvão coloidal (imunohistoquímica). Os dados foram analisados por ANOVA e pós-teste de Tukey. RESULTADOS: SMOF não alterou a quimiotaxia e fagocitose nos leucócitos estudados. TCM/TCL e TCM/TCL/OP aumentaram o número de macrófagos fagocitantes do fígado e pulmão e somente TCM/TCL/OP apresentou aumento no número de macrófagos fagocitantes no baço (p<0,05). CONCLUSÕES: 1) Emulsões lipídicas, independente de sua composição, não influenciaram a quimiotaxia de neutrófilos; 2) Emulsão lipídica composta por mistura de triglicérides de cadeia média e óleos de soja, oliva e peixe apresentou efeito neutro sobre a quimiotaxia, migração espontânea de neutrófilos e recrutamento de monócitos no fígado, pulmão e baço; 3) Emulsão lipídica de mistura física de triglicérides de cadeia média e cadeia longa estimulou o recrutamento de monócitos, com aumento do número de macrófagos fagocitantes no fígado e pulmão; 4) Emulsão lipídica de mistura física de triglicérides de cadeia média e cadeia longa enriquecida com emulsão lipídica de óleo de peixe, estimulou o recrutamento de monócitos, com aumento do número de macrófagos fagocitantes no fígado, pulmão e baço. / RATIONALE: Parenteral lipid emulsions (LE) with fish oil could modulate inflammatory response and promote or maintain immunologic response, but there are insufficient data about the impact on innate immunity cells functions. AIM: To evaluate the effects of endovenous infusion of LE containing mixture of medium-chain triglycerides and soybean, olive and fish oils on leukocytes migration and phagocytosis in rats, compared to a physical mixture of medium and long-chain triglycerides - MCT/LCT LE supplemented or not with fish oil (FO). METHOD: Isogenic Lewis rats (n=40) were submitted to jugular vein catheterization for parenteral access. The animals were randomized in four groups, according to their infusion: group SMOF: LE containing 30% of soybean oil (LCT), 30% MCT, 25% olive oil and 15% fish oil; group MCT/LCT: LE containing MCT and LCT (1:1 v/v); group MCT/LCT/FO: MCT/LCT LE enriched with fish oil based LE (8:2 v/v); group SS: saline. A non-surgical control (CO-NS) was also performed. In the 5th experimental day and after colloidal carbon injection in tail vein, blood and tissue (liver, lung and spleen) samples were collected for chemotaxis assay (adapted Boyden chamber) and colloidal carbon phagocyting-macrophages quantification (immunohistochemistry). ANOVA and Tukey post test were performed. RESULTS: SMOF LE didn?t influence leukocytes chemotaxis and phagocytosis. MCT/LCT and MCT/LCT/FO LE increased liver and lung resident phagocyting-macrophages number (p<0.05) and only in MCT/LCT/FO group, spleen resident phagocyting-macrophages number was increased (p<0.05). CONCLUSION: 1) Lipid emulsion, independently of composition, has no influence on neutrophils chemotaxis; 2) Lipid emulsion with a mixture of medium-chain triglycerides, soybean, olive and fish oils has neutral effect on neutrophil chemotaxis, random migration and monocyte recruitment to the liver, lung and spleen; 3) Lipid emulsion with a physical mixture of medium and long-chain triglycerides has stimulatory effect on monocyte recruitment, with increase of phagocyting-macrophages number in liver and lung; 4) Lipid emulsion with a physical mixture of medium and longchain triglycerides supplemented with fish oil, has stimulatory effect on monocyte recruitment, with increase of phagocyting-macrophages number in liver, lung and spleen.

Orientador: Helena Coutinho Franco de Oliveira / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-11T11:46:21Z (GMT). No. of bitstreams: 1 Raposo_HelenaFonseca_M.pdf: 1257741 bytes, checksum: f53550bd6c88a5cd12f0daf241da3486 (MD5) Previous issue date: 2008 / Resumo: Os óleos de peixe e de milho são fontes de ácidos graxos poli-insaturados (PUFA) n-3 e n-6, respectivamente. Estes ácidos graxos são ligantes naturais dos receptores ativados por proliferadores de peroxissomos (PPARs) e, dessa forma, modificam a expressão de diversos genes envolvidos no metabolismo de lipídios. A proteína de transferência de colesteril-éster (CETP) é uma proteína plasmática sintetizada em vários tecidos, principalmente do fígado. A CETP participa do transporte reverso de colesterol, reduzindo HDL no plasma e aumentando o risco de aterosclerose. Este trabalho teve como objetivo investigar os efeitos dos óleos ricos em PUFA n-3 e n-6 e de fibratos (ligantes sintéticos de PPAR e agentes redutores de triglicérides) sobre a expressão e atividade da CETP. Assim, camundongos transgênicos que expressam a CETP foram tratados por duas semanas com óleo de peixe, óleo de milho ou salina, e camundongos CETP hipertrigliceridêmicos foram tratados com gemfibrozil (GEM), fenofibrato (FENO), bezafibrato (BEZA) ou veículo (control). Após os tratamentos com os PUFA, não foi verificada diferença no peso corporal, na ingestão ou no peso relativo do fígado e tecidos adiposos. Também não houve alteração das concentrações plasmáticas de glicose e triglicerídios. O óleo de peixe reduziu os níveis de ácidos graxos livres (37%) e colesterol (15%), enquanto o óleo de milho aumentou significativamente os níveis de colesterol. Comparado ao grupo salina, os camundongos tratados com óleo de milho apresentaram aumento nos níveis de leptina (30-40%). O tratamento com óleo de peixe elevou os níveis de adiponectina quando comparados com o grupo salina (27%) e com o grupo tratado com óleo de milho (31%). Dois dos três fibratos testados (FENO, GEM) induziram elevação da atividade plasmática (15-30%) e da expressão hepática de RNAm da CETP (53-75%) quando comparados ao grupo controle. FENO também reduziu a concentração plasmática de triglicérides. O óleo de peixe aumentou os níveis plasmáticos de CETP em relação aos grupos salina e óleo de milho (13-14%), efeito verificado apenas nas fêmeas. Entretanto, não foi observada alteração na expressão hepática de RNAm de CETP. Verificou-se que os tratamentos com os óleos PUFA reduziram a expressão hepática de RNAm de PPAR_ (36%) e o óleo de milho induziu aumento da expressão do fator de transcrição SREBP1 (120%) nos machos, mas não nas fêmeas. Os óleos PUFA também induziram aumento da expressão de SREBP2, porém, apenas em fêmeas. As alterações diferenciais de RNAm de PPAR_, SREBP1 e SREBP2 em cada sexo poderiam estar implicadas na resposta gênero-específica da CETP frente aos PUFA. Assim concluímos que o gene da CETP é responsivo aos agonistas sintéticos de PPAR_, e que os ácidos graxos n-3 controlam a expressão da CETP de maneira gênero-dependente e por mecanismo pós-transcricional / Abstract: Fish and corn oils are n-3 and n-6 polyunsaturated fatty acid (PUFA) sources, respectively. They are natural ligands of the peroxisome proliferator activated receptors (PPARs), thus capable of modifying the expression of several genes involved in lipid metabolism. CETP is a plasma protein synthesized in several tissues, mainly liver, which reduces plasma HDL and increases the risk of atherosclerosis. The aim of this work was to investigate the potential effects of PUFA oils and fibrates on the CETP levels. Therefore, CETP transgenic mice were treated during 2 weeks with fish oil (FO), corn oil (CO) or saline, whilst hypertrygliceridemic CETP mice were treated with gemfibrozil (GEM), fenofibrate (FENO), bezafibrate (BEZA) or vehicle (control). There were no differences in body weight, food intake and relative weight of liver and adipose tissue after PUFA or saline treatments. Also, no changes were verified in glucose and triglyceride plasma levels after both PUFA treatments. FO reduced plasma free fatty acid (37%) and cholesterol (15%) levels, whilst CO increased cholesterol mildly. Compared to saline, mice treated with CO showed an increase in leptin levels (30-40%). Treatment with FO enhanced adiponectin plasma levels when compared to saline (27%) and CO (31%). Two out of the three fibrates (FENO, GEM) induced elevation in plasma CETP activity (15- 30%) and liver mRNA expression (53-75%) when compared to control. FENO also reduced triglyceride levels. FO increased CETP plasma levels (13-14%) when compared to CO and saline, an effect verified only in females. However, no changes were observed in liver CETP mRNA expression. FO treatment decreased PPAR_ (36%) and CO increased SREBP1 liver mRNA levels (120%) in males, but not in females. PUFA treatment increased SREBP2 mRNA only in females. These distinct mRNA changes could explain genderspecific CETP response to PUFA treatments. In conclusion, CETP gene is responsive to PPAR_ agonists, and n-3 PUFA (FO) can regulate CETP expression by post-transcriptional mechanisms, in a manner dependent on the female context / Mestrado / Fisiologia / Mestre em Biologia Funcional e Molecular