PUFAs have been shown to modulate ALD by several mechanisms, including free radical generation from hepatic lipid peroxidation. However, how they modulate lipid peroxidation and generation of bioactive metabolites in ALD is poorly understood and it is still not clear which PUFAs (ω-3 or ω-6) are beneficial or detrimental in ALD. Thus, our objective was to study the effect of ω-3/ω-6 PUFAs on lipid peroxidation and ethanol mediated steatosis and inflammation. Using standard liquid diet (LDC), LDC with fish oil (rich in ω-3) and safflower oil (rich in ω-6), we studied the generation of bioactive metabolites, such as eicosanoids and free radicals generated via lipid peroxidation. In addition, we determined the effect of PUFAs on several inflammatory and fibrotic factors, e.g. gene as well as protein expression, using western blot and RT-PCR, respectively. We also investigated the effect of PUFA diets on novel targets, such as hepatic membrane transporters with potential role in liver inflammation. Our results suggest that ω-3 diet prevented while ω-6 based diets promoted the development of fatty liver and inflammation. ω-3 PUFA reduced AA-peroxidation by lowering hepatic AA concentration and expression of peroxidation enzymes, COX-2 and 5-LOX, resulting in lower generation of pro-inflammatory AA-derived PGs (Series-2), HETEs and free radicals, along with increase in anti-inflammatory EPA and DHA-derived PGs (Series-3). ω-3 diet might also reduce liver inflammation by preventing activation of NF-кB and induction of TNF-α. Rats fed with ω-3 diet showed high protein expression of efflux transporters, MRP-2 and ABCA1, indicating elimination of peroxidation metabolites and triglycerides from the liver and decreased inflammation. In contrast, ω-6 diets led to increase in AA-peroxidation and generation of AA-derived pro-inflammatory metabolites. ω-6 based diets also promoted fatty liver and inflammation by activating NF-кB, inducing TNF-α and downregulation of efflux transporters, MRP-2 and ABCA1. This study not only provides new insights into the effects and possible mechanisms by which ω-3 and ω-6 PUFAs may alter hepatic steatosis and inflammation, but also put forward new targets of research, such as hepatic membrane transporters in relation to liver pathology in ALD.

Introducción: Durante los primeros años de vida es fundamental que el niño presente un buen estado nutricional para el adecuado desarrollo cerebral. Al nacer el cerebro humano tiene una infinidad de células que deben interconectarse para funcionar de manera apropiada. Los ácidos grasos esenciales son un componente esencial para el desarrollo neurológico de los niños, este desarrollo según estudios se da hasta los 5 años de edad. Sin embargo, una deficiencia de los ácidos grasos esenciales omega 3 puede repercutir en la conexión sináptica evitando así un buen desarrollo y coeficiente intelectual. Objetivo: Determinar la relación entre el consumo dietario de Omega 3 y el Coeficiente Intelectual en niños y niñas de 30 a 48 meses del distrito Mi Perú, Callao. Diseño: Estudio descriptivo de enfoque cuantitativo, asociación cruzada, transversal y retrospectivo. Participantes: 67 niños y niñas de 30 a 48 meses del distrito Mi Perú, Callao, los cuales fueron elegidos según muestreo aleatorio simple. Intervención: Previo consentimiento informado a las madres de los niños sujetos de estudio se les aplicó una frecuencia semicuantitativa de consumo de alimentos hidrobiológicos el cual contaba con dosificaciones apoyados del laminario PRISMA y tabla de dosificaciones del CENAN para determinar el consumo dietario de omega 3 por día; se aplicó el test de Escala de Inteligencia de Wechsler para preescolar y primaria WPPSIIII para determinar el coeficiente intelectual. Principales medidas de resultados: Relación mediante prueba Razón de verosimilitudes entre el consumo dietario de Omega 3 y el nivel de Coeficiente Intelectual. Resultados: El 85% (n=67) de los niños y niñas de 30 a 58 meses han presentado un consumo dietario adecuado de Omega 3 (>100 mg de DHA+EPA por día) y el 15% (n=67) un consumo dietario deficiente de Omega 3 alimentos fuente de Omega 3 (<100 mg de DHA+EPA por día); en relación al coeficiente intelectual (CI) el 13% (n=67) estuvieron por debajo de lo normal, según prueba de razón de verosimilitudes p valor = 0.038. Conclusiones: Se concluye que existe una relación entre el consumo dietario de Omega 3 y el Coeficiente Intelectual de los niños y niñas de 30 a 48 meses del distrito Mi Perú, Callao. Palabras graves: Omega 3, DHA, Coeficiente intelectual. / --- Introduction: During the first years of life is critical that the children have a good nutritional status for proper brain development. At birth the human brain has an infinite number of cells to be interconnected to function properly. Essential fatty acids are essential for the neurological development of children, this development according to studies is given up to 5 years old. But a deficiency of essential omega 3 fatty acids can affect the synaptic connection avoiding a good development and intelligence quotient (IQ). Objectives: To determine the relationship between dietary intake of Omega 3 and intelligence quotient in children 30 to 48 months from the district Mi Perú, Callao. Design: descriptive study of quantitative approach, cross, cross, retrospective association. Participants: 67 children 30 to 48 months the district Mi Perú, Callao, which were chosen by probability sampling and quota. Interventions: After informed consent mothers of children study subjects were given a semiquantitative frequency of consumption of aquatic foods which had supported the plates' PRISMA dosages and dosages table of CENAN to determine the dietary intake of omega 3 per day; test Wechsler Intelligence Scale for preschool and primary WPPSI-III was used to determine IQ. Main outcome measures: Relationship by Likelihood ratio test between the dietary intake of Omega 3 and IQ level. Results: 85% (n = 67) of children aged 30- 58 months have presented an adequate dietary intake of omega-3 (> 100 mg EPA + DHA per day) and 15% (n = 67) A Poor dietary intake of Omega 3 food source of Omega 3 (<100 mg EPA + DHA per day); in relation to intelligence quotient (IQ) 13% (n = 67) they were below normal, according to the Likelihood Ratio test p value = 0.038. Conclusions: We conclude that there is an association between dietary intake of Omega 3 and IQ of children 30 to 48 months the district Mi Perú, Callao. Keywords: Omega 3, DHA, intelligence quotient

O experimento foi realizado no Biotério Experimental da USP em Pirassununga - SP. Na primeira fase foram utilizados 42 coelhos machos em crescimento da raça Nova Zelândia mantidos individualmente durante todo o experimento. O ensaio biológico totalizou 150 dias. Na Fase 1 os animais receberam dietas com indução de hipercolesterolemia (0,5% de colesterol), com desequilíbrio na proporção de Omega-6/Omega-3 (n-6:n-3) de 15:1 e vice versa e balanço na proporção de n-6:n-3 de 4:1 (controle), totalizando 6 ensaios, os quais foram divididos aleatoriamente em 7 grupos de 6 coelhos cada. Óleos de girassol e de peixe foram utilizados como fontes de ácidos graxos poli-insaturados n-6 e n-3, respectivamente. Na Fase 2, os animais remanescentes continuaram recebendo as mesmas dietas, exceto no grupo B (hipercolesterolemia) que passou a receber o tratamento controle para verificar o efeito. No final da Fase 1, três animais de cada grupo foram eutanasiados com retirada da artéria aorta para determinação de placas lipídicas, histopatológica, colesterol total e imunohistoquímica para verificação da expressão da enzima LDL-receptor e determinação histopatológica do tecido hepático. Em soro foram realizadas determinações de perfil de ácidos graxos, colesterol total, LDL e HDL-colesterol e triacilgliceróis. Células endoteliais aórticas de coelhos foram isoladas para a realização do teste dose resposta com óleo de peixe para identificar a melhor relação do consumo destes ácidos graxos comparando com o experimento in vivo. O objetivo deste trabalho foi monitorar os efeitos do fornecimento de cada dieta sobre o teor de colesterol total, LDLcolesterol, HDL-colesterol e triacilgliceróis em sangue de coelhos. No geral, o perfil de ácidos graxos no soro correspondeu diretamente com a dieta consumida. Os principais efeitos dos ácidos graxos poli-insaturados Omega 3 foi a redução dos lipídios séricos quando os coelhos remanescentes da dieta hipercolesterolêmica (0,5% de colesterol e n-6:n-3 de 2:1) passaram a receber o equilíbrio da relação de ácidos graxos 4:1 de n-6:n-3. O teor de colesterol total no soro, artérias e o crescimento dos ateromas foram influenciados pelo elevado consumo de ácidos graxos n-6 e n-3 associados à adição de colesterol nas dietas. Por outro lado verificamos que o excesso de Omega 3 associado ou não ao colesterol contribuiu para o agravamento das placas ateroscleróticas inclusive deposição de cálcio nas mesmas e paredes endoteliais. Provavelmente, o excesso de n-3 tenha ocasionado efeito contrário às suas funções anti-inflamatória, antiagregatória e anti-trombótica. Dietas hipercolesterolêmicas provocaram esteatose hepática e o elevado consumo de Omega-6 em detrimento do baixo consumo de Omega -3 induziram hepatite crônica. Já o consumo elevado de Omega-3, sem colesterol, regrediu a esteatose hepática nos animais. O consumo equilibrado de n-6:n-3 reduziu a expressão da enzima LDL-receptor no grupo que anteriormente recebeu dieta hipercolesterolêmica. Ressaltando-se a importância do consumo equilibrado destes ácidos graxos já que esta enzima é controlada pelo colesterol livre circulante. No teste dose-resposta em células endoteliais da aorta de coelhos foi evidenciado que a melhor proporção de n-6:n-3 seria de 9 vezes mais do que a concentração de Omega 3 recomendada de 5:1. / The experiment was conducted at the Experimental Biotery by USP in Pirassununga - SP. In the first phase were used 42 male rabbits growing New Zealand breed individually maintained throughout the experiment. The biological assay amounted to 150 days. In phase 1, the animals received diets induced hypercholesterolemia (0.5% cholesterol) with imbalance in the ratio of Omega-6 / Omega-3 (n-6 / n-3) 15:1 and vice versa, and balance the ratio of n-6 / n-3 of 4:1 (control), totaling six tests, which were randomly divided into 7 groups of six rabbits each. Sunflower and fish oils were used as sources of fatty acids polyunsaturated n-6 and n-3, respectively. In Phase 2, the remaining animals continued to receive the same diets except in group B (hypercholesterolemia) who went on to receive the control treatment to check the effect. At the end of Phase 1, three animals from each group were sacrificed with the aorta artery removed for determination of lipid plaques, histopathology, immunohistochemistry and total cholesterol to verify the expression of LDL-receptor enzyme and determination of histopathological liver tissue. In serum profile were made determinations of fatty acids, total cholesterol, LDL and HDL cholesterol and triglycerides. Aortic endothelial cells of rabbits were isolated to perform the dose response test with fish oil to identify the best value for the consumption of these fatty acids compared to the in vivo experiment. The objective of this work was to monitor the effects of provision for each diet on total cholesterol, LDL-cholesterol, HDLcholesterol and triglycerides in the blood of rabbits. In general, the profile of fatty acids in serum corresponded directly with the diet consumed. The main effects of polyunsaturated Omega 3 fatty acids was the reduction of serum lipids when the remaining rabbits with hypercholesterolemic diet (0.5% cholesterol and n-6: n-3 2:1) have received the balance of the relationship fatty acid 4:1 n-6: n-3. The total cholesterol content in serum, the growth of arteries and atheroma were influenced by a high intake of n-6 fatty acids and n-3 associated with the addition of cholesterol in diets. On the other hand we verified that the excess of Omega 3 with or without cholesterol contributed to the aggravation of the atherosclerotic plaques including deposition of calcium in them and endothelial walls. Probably the excess of n-3 has caused the opposite effect to their anti-inflammatory, anti-thrombotic and anti-aggregatory functions. Hypercholesterolemic diets caused hepatic steatosis and high intake of Omega-6 to the detriment of low consumption of Omega -3 induced chronic hepatitis. High consumption of Omega-3, no cholesterol, decreased hepatic steatosis in animals. Highlighting the importance of the balanced intake of this fatty acids, since this enzyme is controlled by circulating free cholesterol. In dose-response test in endothelial cells of the rabbits aorta was evident that the best ratio of n-6: n-3, nine times more than the recommended concentration of Omega 3 to 5:1.

"October 2003" Bibliography: leaves 190-210. Ch. 1. Literature review -- Ch. 2. A practical approach to increasing intakes of n-3 polyunsaturated fatty acids: use of novel foods enriched with n-3 fats -- Ch. 3. Effects of fatty acids on the incidence of arrhythmias in patients with implanted cardioverter-defibrillators (ICDs) -- Ch. 4. A pilot study to investigate the effects of n-3 fatty acids on inducible, sustained ventricular tachycardia in patients undergoing electrophysiology testing -- Ch. 5. Conclusions and future directions.

"October 2003" / Bibliography: leaves 190-210. / xxi, 210 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2003

Thesis (Ph.D.)--University of Nebraska-Lincoln, 2009. / Title from title screen (site viewed October 15, 2009). PDF text: vii, 163 p. : ill. (some col.) ; 7 Mb. UMI publication number: AAT 3369413. Includes bibliographical references. Also available in microfilm and microfiche formats.

Thesis (M. Sc.)--University of Alberta, 2009. / Title from pdf file main screen (viewed on Jan. 11, 2010). "A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Master of Science in Food Science and Technology, Department of Agricultural, Food and Nutritional Science, University of Alberta." Includes bibliographical references.

Thesis (Ph.D.) -- University of Adelaide, Dept. of Medicine, 2003. / "October 2003" Bibliography: leaves 190-210.

Thesis (M.S.)--Brigham Young University. College of Nursing, 2004. / Includes bibliographical references (p. 14-18).

O experimento foi realizado no Biotério Experimental da USP em Pirassununga - SP. Na primeira fase foram utilizados 42 coelhos machos em crescimento da raça Nova Zelândia mantidos individualmente durante todo o experimento. O ensaio biológico totalizou 150 dias. Na Fase 1 os animais receberam dietas com indução de hipercolesterolemia (0,5% de colesterol), com desequilíbrio na proporção de Omega-6/Omega-3 (n-6:n-3) de 15:1 e vice versa e balanço na proporção de n-6:n-3 de 4:1 (controle), totalizando 6 ensaios, os quais foram divididos aleatoriamente em 7 grupos de 6 coelhos cada. Óleos de girassol e de peixe foram utilizados como fontes de ácidos graxos poli-insaturados n-6 e n-3, respectivamente. Na Fase 2, os animais remanescentes continuaram recebendo as mesmas dietas, exceto no grupo B (hipercolesterolemia) que passou a receber o tratamento controle para verificar o efeito. No final da Fase 1, três animais de cada grupo foram eutanasiados com retirada da artéria aorta para determinação de placas lipídicas, histopatológica, colesterol total e imunohistoquímica para verificação da expressão da enzima LDL-receptor e determinação histopatológica do tecido hepático. Em soro foram realizadas determinações de perfil de ácidos graxos, colesterol total, LDL e HDL-colesterol e triacilgliceróis. Células endoteliais aórticas de coelhos foram isoladas para a realização do teste dose resposta com óleo de peixe para identificar a melhor relação do consumo destes ácidos graxos comparando com o experimento in vivo. O objetivo deste trabalho foi monitorar os efeitos do fornecimento de cada dieta sobre o teor de colesterol total, LDLcolesterol, HDL-colesterol e triacilgliceróis em sangue de coelhos. No geral, o perfil de ácidos graxos no soro correspondeu diretamente com a dieta consumida. Os principais efeitos dos ácidos graxos poli-insaturados Omega 3 foi a redução dos lipídios séricos quando os coelhos remanescentes da dieta hipercolesterolêmica (0,5% de colesterol e n-6:n-3 de 2:1) passaram a receber o equilíbrio da relação de ácidos graxos 4:1 de n-6:n-3. O teor de colesterol total no soro, artérias e o crescimento dos ateromas foram influenciados pelo elevado consumo de ácidos graxos n-6 e n-3 associados à adição de colesterol nas dietas. Por outro lado verificamos que o excesso de Omega 3 associado ou não ao colesterol contribuiu para o agravamento das placas ateroscleróticas inclusive deposição de cálcio nas mesmas e paredes endoteliais. Provavelmente, o excesso de n-3 tenha ocasionado efeito contrário às suas funções anti-inflamatória, antiagregatória e anti-trombótica. Dietas hipercolesterolêmicas provocaram esteatose hepática e o elevado consumo de Omega-6 em detrimento do baixo consumo de Omega -3 induziram hepatite crônica. Já o consumo elevado de Omega-3, sem colesterol, regrediu a esteatose hepática nos animais. O consumo equilibrado de n-6:n-3 reduziu a expressão da enzima LDL-receptor no grupo que anteriormente recebeu dieta hipercolesterolêmica. Ressaltando-se a importância do consumo equilibrado destes ácidos graxos já que esta enzima é controlada pelo colesterol livre circulante. No teste dose-resposta em células endoteliais da aorta de coelhos foi evidenciado que a melhor proporção de n-6:n-3 seria de 9 vezes mais do que a concentração de Omega 3 recomendada de 5:1. / The experiment was conducted at the Experimental Biotery by USP in Pirassununga - SP. In the first phase were used 42 male rabbits growing New Zealand breed individually maintained throughout the experiment. The biological assay amounted to 150 days. In phase 1, the animals received diets induced hypercholesterolemia (0.5% cholesterol) with imbalance in the ratio of Omega-6 / Omega-3 (n-6 / n-3) 15:1 and vice versa, and balance the ratio of n-6 / n-3 of 4:1 (control), totaling six tests, which were randomly divided into 7 groups of six rabbits each. Sunflower and fish oils were used as sources of fatty acids polyunsaturated n-6 and n-3, respectively. In Phase 2, the remaining animals continued to receive the same diets except in group B (hypercholesterolemia) who went on to receive the control treatment to check the effect. At the end of Phase 1, three animals from each group were sacrificed with the aorta artery removed for determination of lipid plaques, histopathology, immunohistochemistry and total cholesterol to verify the expression of LDL-receptor enzyme and determination of histopathological liver tissue. In serum profile were made determinations of fatty acids, total cholesterol, LDL and HDL cholesterol and triglycerides. Aortic endothelial cells of rabbits were isolated to perform the dose response test with fish oil to identify the best value for the consumption of these fatty acids compared to the in vivo experiment. The objective of this work was to monitor the effects of provision for each diet on total cholesterol, LDL-cholesterol, HDLcholesterol and triglycerides in the blood of rabbits. In general, the profile of fatty acids in serum corresponded directly with the diet consumed. The main effects of polyunsaturated Omega 3 fatty acids was the reduction of serum lipids when the remaining rabbits with hypercholesterolemic diet (0.5% cholesterol and n-6: n-3 2:1) have received the balance of the relationship fatty acid 4:1 n-6: n-3. The total cholesterol content in serum, the growth of arteries and atheroma were influenced by a high intake of n-6 fatty acids and n-3 associated with the addition of cholesterol in diets. On the other hand we verified that the excess of Omega 3 with or without cholesterol contributed to the aggravation of the atherosclerotic plaques including deposition of calcium in them and endothelial walls. Probably the excess of n-3 has caused the opposite effect to their anti-inflammatory, anti-thrombotic and anti-aggregatory functions. Hypercholesterolemic diets caused hepatic steatosis and high intake of Omega-6 to the detriment of low consumption of Omega -3 induced chronic hepatitis. High consumption of Omega-3, no cholesterol, decreased hepatic steatosis in animals. Highlighting the importance of the balanced intake of this fatty acids, since this enzyme is controlled by circulating free cholesterol. In dose-response test in endothelial cells of the rabbits aorta was evident that the best ratio of n-6: n-3, nine times more than the recommended concentration of Omega 3 to 5:1.