Many populations have low intakes of n-3 fatty acids, yet there is substantial evidence that the long chain n-3 fatty acid docosahexaenoic acid (DHA; 22:6n-3), found at high concentrations in the brain, is required for the proper development of the nervous system. However, less is known about requirements of long chain n-3 fatty acids for maintenance and function of the nervous system in later life. Several recent studies have reported that high amounts of long chain n-3 fatty acids reduce the extent of brain damage caused by cerebral ischemia in animals. However, whether or not a dietary deficiency of n-3 fatty acids increases the extent of injury when cerebral ischemia occurs has not been previously reported. The present studies, therefore, sought to determine if a diet deficient in n-3 fatty acids influences the extent of brain injury in the rat following cerebral ischemia. Male rats were fed an n-3 fatty acid adequate (control), an n-3 fatty acid deficient, or a high DHA diet for 5 weeks from weaning. Middle cerebral artery occlusion (MCAO) was induced and infarct volume was measured by 2,3,5,-triphenyltetrazolium chloride staining 24 hours after the procedure. Brain and platelet fatty acids were analyzed by gas liquid chromatography. DHA (22:6n-3) was 21-28% lower in brain phospholipids, and 17% lower in brain total fatty acids in the n-3 fatty acid deficient compared to control group, while 22:6n-3 was 12% higher in total brain fatty acids in the high DHA group than the control group. There was no significant difference in infarct volume (203, 220 and 218 mm³) among the control, n-3 fatty acid deficient, and high DHA groups, respectively. Platelet fatty acids and platelet aggregation were assessed to determine if these were influenced by the high DHA diet, and could possibly explain the observation of an apparent, but not statistically significant, higher number of rats with hemorrhages in the high DHA diet group. Platelet lipid arachidonic acid was not lower and platelet aggregation, assessed ex vivo using whole blood with a platelet function analyzer, was not longer in rats fed the high DHA compared to control or n-3 fatty acid deficient diets. In summary, dietary n-3 fatty acid deficiency did not increase the extent of brain injury following cerebral ischemia. The possibility that high dietary 22:6n-3 might increase susceptibility to cerebral hemorrhage will require further study. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

The American Heart Association recommends consuming fish (particularly oily fish) at least two times per week, which would provide ae 0.5 g/day of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) for cardiovascular disease risk reduction. Previous analyses indicate that this recommendation is not being met; however, few studies have assessed different ethnicities, subpopulations requiring additional n-3 fatty acid intake (i.e., children and pregnant and/or lactating women), or deciles of intake. Data from the National Health and Nutrition Examination Survey 2003-2008 was used to assess n-3 fatty acid intake from foods and supplements in the US population, according to age, sex, and ethnicity. A unique "EPA equivalents" factor, which accounts for potential conversion of shorter-chain n-3 fatty acids, was used to calculate total long-chain n-3 fatty acid intake. Data are reported for 24,621 individuals. More than 90% consumed less than the recommended 0.5 g/day from food sources (median = 0.11 g/day; mean = 0.17 g/day). Among the top 15% of n-3 fatty acid consumers, fish was the largest dietary contributor (71.2%). Intake was highest in men aged 20 years or more, and lowest in children and women who are or may become pregnant and/or are lactating. Among ethnicities, intake was lowest in Mexican-Americans. Only 6.2% of the total population reported n-3 fatty acid supplement use, and this did not alter median daily intake. Additional strategies are needed to increase awareness of health benefits (particularly among Mexican-Americans and women of childbearing age) and promote consumption of oily fish or alternative dietary sources to meet current recommendations.

No description available.

1 Abstract In this thesis I have focused on the role of lipids in the pathogenesis of liver diseases, specifically on cholestasis and non-alcoholic fatty liver disease (NAFLD). The first major aim was to clarify the changes in liver ganglioside metabolism in various types of cholestasis and to elucidate the role of heme oxygenase-1 (HMOX1) and associated oxidative stress. The second objective was to determine the effects of n-3 polyunsaturated fatty acids (n-3 PUFA) administration on NAFLD development in a rodent dietary model of NAFLD and in patients with metabolic syndrome and NAFLD. Our results suggest that increased ganglioside biosynthesis and their re-distribution might represent a general protective mechanism of hepatocytes under cholestatic conditions (both estrogen-induced and obstructive aetiology). These changes are closely related to oxidative stress and might protect hepatocytes against deleterious effect of accumulated bile acids. The lack of HMOX1 activity and subsequent oxidative stress potentiate pathological changes in the liver and resulted in tissue-specific modulation of synthesis and re-distribution of gangliosides (in vivo and in vitro). Contrary to it, HMOX1 activation has an opposite effect and may represent a general hepatoprotective mechanism. We have proven that observed changes...

Marine oils are used as ration additives to provide omega-3 fatty acids to dairy cows. Supplementing dairy cows with omega-3 fatty acid-rich feeds does not easily increase quantities in milk fat of dairy cows because polyunsaturated fatty acids are biohydrogenated in the rumen. Lipid encapsulation of omega-3 fatty acids provides protection from biohydrogenation in the rumen and allows them to be available for absorption and utilization in the small intestine. Lactating cows were supplemented with rumen protected algae biomass or algal oil in a 4 × 4 Latin Square. Feeding lipid encapsulated algae supplements increased docosahexaenoic acid content in milk fat while not adversely impacting milk fat yield; however, docosahexaenoic acid was preferentially esterified into plasma phospholipid, limiting its incorporation into milk fat. In the second study, triglyceride emulsions of oils enriched in either oleic, linoleic, linolenic, or docosahexaenoic acids were intravenously infused to avoid confounding effects of triglyceride esterification patterns in the small intestine and to compare mammary uptake. Milk transfer of fatty acids delivered as intravenous triglyceride emulsions was reduced with increased chain length and unsaturation. Increased target fatty acids were evident in plasma phospholipid, suggesting re-esterification in the liver. Transfer efficiencies were 37.8, 27.6, and 10.9±5.4% for linoleic, linolenic, and docosahexaenoic acid. Both liver and mammary mechanisms may regulate transfer of long-chain polyunsaturates. Intracellular fatty acid binding proteins (FABP) are cytoplasmic proteins that are hypothesized to be essential for fatty acid transport and metabolism by accelerating longchain fatty acid uptake and targeting to intracellular organelles, such as the endoplasmic reticulum for triglyceride esterification. FABP3 mRNA is highly expressed in bovine mammary and heart tissue, but is not present in MAC-T cells, a bovine mammary epithelial cell line. When overexpressed in MAC-T cells, FABP3 does not appear to be rate-limiting for fatty acid uptake in vitro and did not alter lipid metabolism. The function of FABP3 in the mammary gland remains unclear. / Ph. D.

The tumor microenvironment is a well-recognized contributor to cancer progression in solid tumors. Cancer cell interactions with abnormal extracellular matrix, tumor associated immune and stromal cells, and aberrant fluid flow all contribute to cancer progression. Breast tumors are often characterized by a dense collagenous stroma and a hypoxic core. A recently identified and little understood component of the breast tumor microenvironment is the breast microbiome. The work described here elaborates on the importance of the tumor microenvironment in cancer progression and demonstrates the importance of studying cancer-microbiome interactions in the context of tumor microenvironmental stimuli. / Master of Science / One of the major barriers to effective cancer treatment is the environment is which cancer grows. Tumors insulate themselves in a thick protein structure that leads to a stiffening of the breast tissue. In addition, irregular tumor-associated blood vessels lead to poor blood flow, and therefore a lack of oxygen, in the center of the tumor. These and other characteristics of tumors create an environment in which cancer cells are resistant to current anti-cancer therapies and thereby allows them to flourish. It was recently discovered that, contrary to previous belief, there are resident bacteria present in normal and cancerous breast tissue. The role they play in controlling cancer development and progression in the tumor is unknown. The work described here elaborates on the tumor environmental barriers to current anti-cancer therapies and shows how one bacterial produced compound may interact with other features of the tumor environment in order to control breast cancer survival.

Les acides gras polyinsaturés à longue chaîne (AGPI-LC) de la série n-3 jouent des rôles essentiels dans le fonctionnement du cerveau et notamment dans les processus de plasticité synaptique et de mémoire, altérés au cours du vieillissement. Il est maintenant bien admis que ces AGPI peuvent réguler la transcription génique en se liant à des récepteurs nucléaires spécifiques, les PPAR (peroxisome proliferator-activated receptors), mais aussi aux récepteurs de l’acide 9-cis rétinoïque, les RXR (retinoid X receptors). En tant que partenaires communs d’hétérodimérisation des PPAR et des RAR (récepteurs de l’acide tout-trans rétinoïque), les RXR sont des acteurs clés de la modulation de l’expression génique par les acides gras et les rétinoïdes. Dans ce contexte, l’objectif de ce travail de thèse était d’étudier, au cours du vieillissement chez le rat, les effets d’une supplémentation en AGPI-LC n-3 sur l’activité des voies de signalisation des acides gras et des rétinoïdes, les processus de plasticité cérébrale (plasticité synaptique et neurogenèse) et la mémoire spatiale. Nos principaux résultats montrent qu’une supplémentation en AGPI-LC n-3, pendant 21 semaines chez des rats à mi-vie, maintient dans l’hippocampe les niveaux d’expression des ARNm codant pour RXRγ et GAP-43 (protéine synaptique) altérés au cours du vieillissement. De plus les rats âgés supplémentés en AGPI-LC n-3 présentent une augmentation du nombre de néo-neurones hippocampiques et une amélioration de la mémoire spatiale de travail, comparés aux rats âgés contrôle. Les résultats de cette étude plaident en faveur d’un effet bénéfique des AGPI-LC n-3 sur la mémoire de travail au cours du vieillissement via notamment, une action sur la plasticité cérébrale. De plus, nos travaux suggèrent l’implication des RXR dans l’effet neuroprotecteur des AGPI-LC n-3, qui réguleraient l’expression de certains gènes cibles impliqués dans la plasticité synaptique et les processus de neurogenèse hippocampique. / Long chain polyunsaturated fatty acids (LC-PUFA) of the n-3 series play essential roles in brain functions, including brain plasticity and memory processes which are altered during aging. It is now well accepted that these PUFA regulate gene transcription through binding and activating specific nuclear receptors such as PPAR (peroxisome proliferator-activated receptors) and RXR (retinoid X receptors, which also bind 9-cis retinoic acid). As a common heterodimeric partner of both PPAR and RAR (all-trans retinoic acid receptors), RXR is a key factor in the modulation of gene expression by fatty acids and retinoids. In this context, the purpose of this work was to study the effects of a n-3 LC-PUFA supplementation on fatty acid and retinoid signalling pathways and on cerebral plasticity and spatial memory processes. Our main results show that n-3 LC-PUFA supplementation for 21 weeks in mid-life rats, maintains the mRNA levels of RXRγ and GAP-43 (synaptic protein) which were altered in aged rat hippocampus. Besides, supplemented aged rats exhibited increased numbers of newly generated neurons and improved spatial working memory, when compared with control aged rats. To summarize, our results support the neuroprotective effects of n-3 LC-PUFA during aging, in particular on cerebral plasticity and working memory. Furthermore, our works suggest the implication of RXR in the set up of these effects through notably the regulation of some target genes involved in synaptic plasticity and hippocampal neurogenesis processes.

La maladie d'Alzheimer (MA) est une démence neurodégénérative caractérisée par des pertes de la mémoire et des troubles cognitifs. La toxicité des oligomères solubles du peptide [bêta]-amyloïde (A[bêta]Os) est centrale dans la phase précoce de la maladie. L'absence de traitements curatifs, l'aspect chronique des mécanismes pathogéniques et le partage de facteurs de risque communs avec les pathologies cardiovasculaires, notamment les paramètres alimentaires et le métabolisme lipidique, doivent inciter à considérer l'intérêt de méthodes préventives permettant d'empêcher l'apparition de la maladie. Dès lors, l'approche nutritionnelle apparaît comme une stratégie capable de limiter sa prévalence. Une souris modèle des stades précoces de MA nous a permit d'évaluer le potentiel préventif d'une alimentation enrichie en acide docosahexaénoïque (DHA, C22:6, n-3). Les résultats obtenus montrent qu'un apport alimentaire suffisant en DHA conduit à en enrichir les membranes dans les différentes structures cérébrales. En conséquence, les fonctions synaptiques sont préservées, même après exposition aigüe aux A[bêta]Os, ce qui maintient les capacités cognitives des souris exposées. Nous avons ensuite développé des stratégies nutritionnelles permettant d'évaluer les effets bénéfiques de DHA contre la dyslipidémie induite par l'alimentation et les déficits cognitifs associés au vieillissement normal ou pathologique. Les résultats obtenus à l'issue de notre étude révèlent qu'un apport alimentaire en DHA est capable de prévenir la dyslipidémie provoquée par un régime riche en lipides et de retarder le déclin cognitif lié au vieillissement cérébral normal ou pathologique / Alzheimer's disease is a neurodegenerative aging-related dementia that is characterized by loss of memory and cognitive disorders. Toxicity of soluble oligomers of [beta]-amyloid peptide (sOA[beta]) is a key element in early stages of the disease. Absence of curative therapies, chronic aspects of the pathogenic mechanisms implicated and influence of common risk factors shared with the cardiovascular diseases, including dietary parameters and lipid metabolism, should widely encourage considering the interest of preventive interventions allowing slowing the progression and delaying the clinical onset of Alzheimer's-related troubles. Therefore, nutritional approaches could appear as a strategy able to reduce the prevalence of this disease. Early Alzheimer's mouse model allowed us to assess the preventive potential of diets supplemented in docosahexaenoic acid (DHA, C22:6 n-3). Our results show that adequate dietary intake of DHA lead to increased levels in different brain structures. Consequently, hippocampal and cortical synaptic functions were preserved, even upon acute exposure to A[beta] oligomers, maintaining or improving the cognitive capacities of A[beta]-exposed mice. These improvements were positively correlated with DHA-enrichment associated in hippocampus and with preserved synaptic integrity. We also designed nutritional strategies in order to evaluate the beneficial effects of DHA on diet-induced dyslipidemia as well as on cognitive impairment and neurodegenerative processes associated with normal or pathologic aging. Our results show that dietary DHA can prevent high-fat diet-induced dyslipidemia and delay cognitive decline related with normal or pathological aging

Les aliments riches en acides gras polyinsaturés (AGPI) à longue chaîne (LC) de la série n-3 sont recommandés pour leurs effets bénéfiques sur la santé humaine et en particulier dans la prevention du développement des maladies métaboliques. Or, la biodisponibilité de ces AGPI et leur impact métabolique pourraient être modulés par la nature chimique des molécules qui les véhiculent dans les aliments (triacylglycérols, TG ou phospholipides, PL). De plus, ces AGPI sont sensibles à la peroxydation lipidique. S’ils ne sont pas protégés de l’oxydation, ils peuvent former des espèces réactives toxiques comme le 4-hydroxy-hexénal (4-HHE). Dans ce contexte, le but de notre étude a été d’évaluer l’impact de l’enrichissement de régimes hyperlipidiques en AGPI n-3 (i) portés par des TG ou des PL et (ii) sous forme non-oxydée ou oxydée, sur l’inflammation et le stress oxydant métaboliques et d’en comprendre certains mécanismes liés à l’absorption intestinale et la réactivité du 4-HHE. D’une part, notre étude a confirmé que la consommation d’AGPI-LC n-3 empêche l’induction du stress oxydant et de l’inflammation lors d’un régime hyperlipidique chez la souris. Cependant, par rapport aux TG, les PL vecteurs d’AGPI n-3 permettent de réduire la taille des adipocytes et de stimuler le système antioxydant. D’autre part, notre étude a montré que la consommation d’AGPI n-3 oxydés de manière modérée aboutit à une élévation des concentrations plasmatiques de 4-HHE et des marqueurs inflammatoires. De plus, une activation des voies inflammatoires ainsi que du stress du réticulum endoplasmique ont été détectées au niveau de l’intestin grêle. Nos résultats in vivo et in vitro sur cellules intestinales Caco-2/TC7 indiquent que cela peut être dû en partie à une absorption au niveau intestinal du 4-HHE, produit d’oxydations des AGPI n-3. Dans le contexte du développement des aliments contenant des AGPI-LC n-3, nos résultats contribuent à identifier les structures vectrices de ces acides gras les plus efficaces du point de vue métabolique. En santé publique et en pratique clinique, nos résultats constituent une nouvelle base de réflexion pour la mise en place de bonnes pratiques de production et de conservation des aliments et des compléments nutritionnels enrichis en AGPI-LC n-3 pour éviter leur oxydation et ses possibles effets délétères. / Dietary intake of n-3 long chain (LC) polyunsaturated fatty acids (PUFA) are recommended for their beneficial effects on human health, especially to prevent the development of metabolic diseases. However, the bioavailability of these PUFAs and their metabolic impact could be modulated by their chemical carriers (triacylglycerols, TG or phospholipids, PL). In addition, these PUFA are susceptible to lipid peroxidation. If they are not protected from oxidation, they can form toxic reactive species such as 4-hydroxy-hexenal (4-HHE). In this context, the aim of our study was to evaluate the impact of enriching high-fat diets with n-3 PUFA (i) bound to TG or PL and (ii) in unoxidized or oxidized form on the generation of inflammation and oxidative stress, and to understand some underlying mechanisms associated with intestinal absorption and reactivity of 4-HHE. On the one hand, our study confirmed in mice that the consumption of n-3 PUFA protects against oxidative stress and inflammation induced by high-fat diets. However, compared to TG, n-3 PUFA in the form of PL reduce the size of adipocytes and stimulate the antioxidant system. On the other hand, our study showed that the consumption of moderately oxidized n-3 PUFA results in increased plasma concentrations of 4-HHE and of inflammatory markers. In addition, activation of inflammatory pathways as well as endoplasmic reticulum stress were detected in the small intestine. Our results in vivo and in vitro, using intestinal Caco-2/TC7 cells, indicate that this can be partly due to the intestinal absorption of the end-product of n-3 PUFA oxidation, 4-HHE. In the context of the development of foods containing LC n-3 PUFA, our results contribute to identify the most effective PUFA carriers on a metabolic standpoint. Regarding public health and clinical practice, our results provide new basis for the set up of best practices regarding production and storage of food and supplements enriched with LC n-3 PUFA to avoid their lipid oxidation and its possible deleterious effects.

L’obésité est associée à un état inflammatoire chronique de bas grade ainsi qu’à descomplications métaboliques secondaires telles que l’insulino-résistance, l’intolérance au glucose etla stéatose hépatique. La composition bactérienne intestinale semble tenir une place importantedans l’apparition de ces complications. Il a en effet été montré qu’une altération du microbiote parun régime obésogène était associée à une endotoxémie métabolique caractérisée par uneaugmentation des concentrations circulantes de lipopolysaccharides bactériens. Les AGPI enn-3 possèdent des propriétés anti-obésogènes et anti-inflammatoires qui pourraient passer par unemodulation du microbiote intestinal et une prévention de l’endotoxémie métabolique. Nous avonsmontré que des souris transgéniques fat-1, présentant des teneurs tissulaires en AGPI enn-3 élevées, soumises durant 18 semaines à un régime obésogène, étaient résistantes à l’obésité etaux troubles métaboliques associés. Ces animaux présentent un maintien de la fonction barrièreintestinale et une prévention de l’endotoxémie métabolique. De plus, une analyse du microbiotecaecal révèle une augmentation du phylum Akkermansia. Enfin, nous avons montré qu’un transfertde matériel fécal de souris fat-1 à des souris sauvages maintenues sous régime obésogène protègeces dernières du développement d’une obésité et des comorbidités associées. Ainsi, uneaugmentation de la teneur en Akkermansia au niveau intestinal par les AGPI en n-3, peutreprésenter une stratégie intéressante de prévention de l’obésité, ainsi que de l’insulino-résistance,l’intolérance au glucose et la stéatose hépatique qui lui sont associées. / Obesity is associated with chronic low-grade inflammatory state and secondary metabolicdisorders, such as insulin-resistance, glucose intolerance and hepatic steatosis. Gut microbiotaseems to play an important role in these obesity features. Moreover, microbiota dysbiosis has beenshown to be associated with increased systemic lipopolysaccharides levels, called metabolicendotoxemia. N-3 PUFAs are anti-obesity and anti-inflammatory molecules able to modulate gutmicrobiota and prevent metabolic endotoxemia. We showed that fat-1 transgenic mice,endogenously synthetizing n-3 PUFAs, resist to obesity development and comorbidities whensubmitted to diet-induced obesity for 18 weeks. These mice exhibit a maintained intestinal barrierfunction and a prevention of metabolic endotoxemia. Moreover, cecal microbiota analysis revealedan increase of Akkermansia phylum. Microbiota transplantation of fat-1 mice to wild type micewas shown to exert protective effects against diet-induced obesity and associated disorders. Thus,increasing gut microbiota Akkermansia population by appropriate n-3 PUFAs may represent apromising strategy to prevent obesity, insulin-resistance, glucose intolerance and hepatic steatosis.