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Growing evidence suggests that obesity and associated metabolic dysregulation occurs in concert with chronic low-grade inflammation. Toll-like receptors (TLR) are transmembrane receptors that play an important role in innate immunity and the induction of inflammatory responses. Our laboratory has observed that TLR4 expression is elevated in the skeletal muscle of obese humans and is associated with reduced fatty acid (FA) oxidation and increased lipid synthesis. Additionally, activation of this pathway by lipopolysaccharide (LPS), ex vivo, results in a shift in substrate metabolism favoring glucose as an energy substrate and preferential storage of FA in intracellular lipid depots. The purpose of this study was to examine the effects of saturated vs. monounsaturated FA on TLR4 transcription and signaling using ex vivo and in vivo models. C2C12 myotubes were incubated in FA-enriched growth medium with varying ratios of palmitate and oleate for 12 hours. Following FA treatment, cells were either collected for measures of mRNA and protein levels of TLR4 or challenged with LPS (500 ng/mL) for 2 hours to assess TLR4 mediated changes in interleukin-6 (IL-6) and glucose and fatty acid metabolism. TLR4 mRNA and protein content were increased in stepwise fashion with higher palmitate concentration (p<0.05). This was associated with an exacerbated LPS effect on IL-6 mRNA and protein levels, and glucose and fatty acid metabolism. To determine if these effects are translated to an in-vivo model, C57BL/6 mice were fed high saturated fat (HSF), high monounsaturated fat (HMF), and control diets for 10 weeks. Following the dietary intervention, animals were challenged with I.P. injections of either saline or LPS (~25μg/mouse), sacrificed 4 hours post-injection, and red and white gastrocnemius muscle were harvested for measures of expression and protein levels of TLR4 and IL-6, and glucose and fatty acid metabolism. TLR4 mRNA and protein levels were not altered with either the HSF or HMF diets. However, there was a heightened LPS response with regards to increases in IL-6 and TNF-α, and enhanced shifts in substrate metabolism following the HSF diet (p<0.05). These effects were not observed in response to the HMF diet. In conclusion, these data demonstrate that a milieu of high saturated fatty acids results in elevated sensitization of the TLR4 pathway in skeletal muscle. These results provide insight into how a westernized diet, one enriched in saturated fat, may link chronic inflammation with obesity-associated metabolic abnormalities. / Ph. D.

No / Chronic wounds often result from prolonged inflammation involving excessive polymorphonuclear leukocyte activity. Studies show that the omega-3 polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids found in fish oils generate bioactive lipid mediators that reduce inflammation and polymorphonuclear leukocyte recruitment in numerous inflammatory disease models. The purpose of this study was to test the hypotheses that boosting plasma levels of eicosapentaenoic and docosahexaenoic acids with oral supplementation would alter lipid mediator levels in acute wound microenvironments and reduce polymorphonuclear leukocyte levels. Eighteen individuals were randomized to 28 days of either eicosapentaenoic + docosahexaenoic acid supplementation (Active Group) or placebo. After 28 days the Active Group had significantly higher plasma levels of eicosapentaenoic (p<0.001) and docosahexaenoic acid (p<0.001) than the Placebo Group and significantly lower wound fluid levels of two 15-lipoxygenase products of omega-6 polyunsaturated fatty acids, [9- hydroxyoctadecadienoic (HODE) acid (p = 0.033) and15-hydroxyeicosatrienoic acid (HETrE) (p = 0.006)], at 24 hours post wounding. The Active Group also had lower mean levels of myeloperoxidase, a leukocyte marker, at 12 hours and significantly more re-epithelialization on Day 5 post wounding. We suggest that lipid mediator profiles can be manipulated by altering polyunsaturated fatty acid intake to create a wound microenvironment more conducive to healing.

by Kwan Kwok Yiu. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (leaves 145-155). / Acknowledgment --- p.i / Abstract --- p.ii / List of Tables --- p.vii / List of Figures --- p.x / List of Abbreviations --- p.xii / Chapter Chapter 1 --- Literature review / Chapter 1.1 --- Historical background --- p.1 / Chapter 1.2 --- Chemistry of trans and cis fatty acids --- p.3 / Chapter 1.3 --- Dietary source of trans fatty acids --- p.6 / Chapter 1.4 --- Consumption of trans fatty acids among Western countries --- p.9 / Chapter 1.5 --- Current health concern for excessive intake of trans fatty acids --- p.10 / Chapter 1.6 --- Metabolism of trans fatty acids --- p.13 / Chapter 1.6.1 --- Absorption --- p.15 / Chapter 1.6.2 --- Oxidation --- p.15 / Chapter 1.6.3 --- Incorporation --- p.16 / Chapter 1.6.4 --- Selectivity --- p.17 / Chapter 1.7 --- Impact of trans fatty acids on essential fatty acid metabolism --- p.19 / Chapter 1.8 --- Desaturation and elongation of trans fatty acids --- p.21 / Chapter 1.9 --- Trans fatty acids and neonatal growth --- p.23 / Chapter Chapter 2 --- Amount of trans fatty acids in Hong Kong fast foods / Chapter 2.1 --- Introduction --- p.25 / Chapter 2.2 --- Objective --- p.25 / Chapter 2.3 --- Materials and methods --- p.26 / Chapter 2.4 --- Results --- p.27 / Chapter 2.5 --- Discussion --- p.31 / Chapter Chapter 3 --- Cross-cultural study of trans fatty acids in human milk / Chapter 3.1 --- Introduction --- p.35 / Chapter 3.2 --- Objective --- p.35 / Chapter 3.3 --- Materials and methods --- p.36 / Chapter 3.4 --- Results / Chapter 3.4.1 --- Dietary information --- p.38 / Chapter 3.4.2 --- Fatty acid composition of Chinese and Canadian human milk --- p.40 / Chapter 3.4.3 --- Difference between Chinese and Canadian human milk --- p.40 / Chapter 3.4.4 --- Difference between Hong Kong and Chongqing Chinese human milk --- p.43 / Chapter 3.4.5 --- The change in milk fat and LCPUFA as lactation progresses --- p.43 / Chapter 3.5 --- Discussion / Chapter 3.5.1 --- Trans fatty acids in human milk --- p.46 / Chapter 3.5.2 --- Content of LCPUFA in human milk --- p.47 / Chapter 3.5.3 --- Content of 18:2n-6 in human milk --- p.48 / Chapter 3.5.4 --- Fat content in Hong Kong and Chongqing Chinese human milk --- p.49 / Chapter 3.6 --- Conclusion --- p.50 / Chapter Chapter 4 --- Trans fatty acids and maternal and neonatal essential fatty acid metabolism / Chapter 4.1 --- Introduction --- p.51 / Chapter 4.2 --- Objectives --- p.53 / Chapter 4.3 --- Materials and methods --- p.53 / Chapter 4.4 --- Results / Chapter 4.4.1 --- Experiment1 / Chapter 4.4.1.1 --- Relationship between the trans fatty acids in maternal diet and those in milk --- p.64 / Chapter 4.4.1.2 --- Relationship between the trans fatty acids in maternal diet and those in neonatal liver --- p.64 / Chapter 4.4.1.3 --- Content of 20:4n-6 in milk and in neonatal liver relative to that in maternal diet --- p.72 / Chapter 4.4.2 --- Experiment2 / Chapter 4.4.2.1 --- Amount of trans fatty acids in rat milk --- p.75 / Chapter 4.4.2.2 --- Trans fatty acids in rat liver phospholipids --- p.75 / Chapter 4.4.2.3 --- Linoleic acid (18:2n-6) content in rat and its relation to maternal diets --- p.86 / Chapter 4.4.2.4 --- Content of 20:4n-6 in rat milk --- p.86 / Chapter 4.4.2.5 --- Content of20:4n-6 in rat liver --- p.89 / Chapter 4.4.2.6 --- Suppression of the synthesis of 20:4t isomers in maternal and neonatal liver --- p.89 / Chapter 4.5 --- Discussion / Chapter 4.5.1 --- Relationship between fatty acid composition of diet and that of milk --- p.93 / Chapter 4.5.2 --- 20:4n-6 in rat milk --- p.95 / Chapter 4.5.3 --- Transfer of trans fatty acids from maternal diet to neonatal liver phospholipids --- p.98 / Chapter 4.5.4 --- The inhibitory effect of trans fatty acids on synthesis of 20:4n-6 in neonatal liver --- p.99 / Chapter 4.5.5 --- Effect of 18:2n-6 supplement on 20:4n-6 level of neonatal liver --- p.101 / Chapter 4.5.6 --- Suppression of 18:2n-6 supplement on synthesis of 20:4t isomers --- p.101 / Chapter 4.6 --- Conclusion --- p.104 / Chapter Chapter 5 --- Accumulation and turnover of trans fatty acids / Chapter 5.1 --- Introduction --- p.105 / Chapter 5.2 --- Objective --- p.105 / Chapter 5.3 --- Materials and methods --- p.106 / Chapter 5.4 --- Results / Chapter 5.4.1 --- Accumulation of trans fatty acids in liver and adipose tissue --- p.108 / Chapter 5.4.2 --- Selectivity of individual 18:2 trans isomersin liver and adipose tissue --- p.112 / Chapter 5.4.3 --- Turnover of trans fatty acids --- p.112 / Chapter 5.4.4 --- Accumulation and turnover of 18:lt in brain --- p.115 / Chapter 5.5 --- Discussion / Chapter 5.5.1 --- Accumulation of trans fatty acids in liver and adipose tissue --- p.120 / Chapter 5.5.2 --- Turnover of trans fatty acids --- p.122 / Chapter 5.5.3 --- Accumulation and turnover of trans fatty acidsin brain --- p.124 / Chapter 5.6 --- Conclusion --- p.125 / Chapter Chapter 6 --- In vivo Oxidation of trans fatty acids in rat / Chapter 6.1 --- Introduction --- p.126 / Chapter 6.2 --- Objective --- p.127 / Chapter 6.3 --- Materials and methods --- p.127 / Chapter 6.4 --- Results --- p.129 / Chapter 6.4.1 --- Apparent oxidation of saturated fatty acids --- p.136 / Chapter 6.4.2 --- Apparent oxidation of 18:lt relative to 18:ln-9 --- p.136 / Chapter 6.4.3 --- Oxidation of 18:2t isomers relative to 18:2n-6 --- p.137 / Chapter 6.4.4 --- Effect of 18:2n-6 supplement in PHCO diet on oxidation per se --- p.137 / Chapter 6.5 --- Discussion --- p.138 / Chapter 6.5.1 --- Oxidation of 18:lt and 18:2t isomers --- p.139 / Chapter 6.5.2 --- Effect of 18:2n-6 supplement on oxidation per se --- p.140 / Chapter 6.6 --- Conclusion --- p.141 / General conclusion --- p.142 / References --- p.145

The regulation of glucagon-like peptide-1 and peptide YY hormone levels are regulated based on different influential factors, but primarily levels are dependent upon ingested food content. As meals today become more fat-enriched, there is greater requirement for evaluation of these hormones that regulate insulin and satiety levels within the body. We have shown that the gene expression transcript production of glucagon-like peptide-1 and peptide YY are modulated by different concentrations, and times of short-chain fatty acids and long-chain fatty acids. Although the peptide hormone levels have the influential physiological role on effector tissue, the regulation of these hormones begins at the transcript levels. Recent research indicates that glucagon-like peptide-1 and peptide YY hormones are altered in response to different free-fatty acids. The present investigation generally demonstrated an overall decrease in both hormones after chronic exposure to fatty acids. Intestinal secretin tumor cell line (STC-1 cells) was used as a representative for intestinal L-cells. Quantitative real-time PCR analysis was used to determine the changes in RNA transcripts. Overall, there was a decrease in the 3-hour timeline, which continued to decrease in the 16-hour and 24-hour timelines for glucagon-like peptide-1. Peptide YY transcript expression in 3-hours increased significantly after exposure to propionate, a significant decrease after exposure to acetate, and no significant increase or decrease after exposure to butyrate. However, there was a significant decrease in peptide YY once reaching 24-hour exposure. It was determined there is a threshold for different concentrations of free-fatty acids to influence glucagon-like peptide-1 and peptide YY production, which was present in the different concentrations of butyrate. Lastly, exposure to both concentrations of linolenic acid caused a significant decrease in glucagon-like peptide-1 and peptide YY.

Charles University Faculty of Pharmacy in Hradec Králové Department of Biophysics and Physical Chemistry Candidate: Monika Novotná Supervisor of Diploma Thesis: Mgr. Monika Kuchařová, Ph.D. Title of Diploma Thesis: The determination of fatty acid levels in the tissues of healthy, suddenly deceased persons and polymorbid patients The aim of the thesis was to determine the levels of 14 fatty acids in tissues of suddenly deceased, otherwise healthy individuals and in the group of polymorbid, chronic patients. It was a comparison of fatty acid levels in seven tissues of the human body: subendocardial left ventricular tissue, liver parenchyma tissue, kidney cortex, adrenal tissue, skeletal muscle, abdominal subcutaneous adipose tissue, and brain tissue. Each group included 10 deceased patients. The theoretical part incudes fatty acids as the main component of lipids. It deals mainly with the group of polyunsaturated fatty acids and their relation to pathologies in the human body. Gas chromatography, thanks to which we analyzed the fatty acid spectrum, is also described. The experimental part consists of the basic characteristics of the research groups, the description of the workflow and the results. Statistically processed data are divided into categories by individual fatty acids and other monitored...

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Diet fatty acids (FA) are fundamental to the phospholipids structure and function of cell membranes, in which long chain polyunsaturated FA (PUFA) increase its fluidity, while the trans FA (TFA) to make it more rigid. Also, the barrier function and hydration are highly dependent on the skin composition and structure, as well as the organization of lipids in the cell matrix. In recent years, the ozone layer depletion has increased human exposure to ultraviolet radiation (UVR), inducing deleterious effects on skin homeostasis. Moreover, lifestyle habits and eating patterns, especially in Western countries, has shown an increasing consumption of processed foods rich in AGT, whose cutaneous consequences do not present scientific validation. Whereas the skin health is partially related to the lipids that compose it, this study was designed to evaluate the effect of supplementation of different oils or fat in distinctlife periods of rodents on oxidative damage acute and chronic exposure to UVR-induced. Male Swiss mice weanling were supplemented daily (3g/kg, po) with soybean oil (C-SO; rich in n-6 PUFA), fish oil (FO; rich in n-3 PUFA) or hydrogenated vegetable fat (HVF; rich in TFA) until 90 days old and the dorsal skin was acutely exposed to UVR. The FO supplementation showed n-3 PUFA incorporation in mice skin, while the groups supplemented with soybean oil and HVF showed incorporation of n-6 PUFA and TFA, respectively. Such skin incorporations exerted influences on the development of UVR -induced oxidative damage in the mice skin and HVF group showed the highest protein carbonylation (PC) levels and lipid peroxidation, accompanied by larger skin thickening (edema), lower catalase (CAT) activity and cell survival. While soybean oil was associated with a partial prevention of damage observed in HVF group, FO supplementation prevented cutaneous oxidative damage UVR-induced. Sequentially, second and third experimental protocols were developed with the first and second generations offsprings born adult rats under daily supplementation of the same oils used in experiment 1 (SO, FO and HVF) and at 90 days old, each experimental group were exposed to UVR 3x/ week for 12 weeks. Animals first generation offspring (experiment 2) FO supplemented treated showed higher incorporation of n-3 FA and lower n-6/n-3 ratio in the dorsal skin, while the HVF group showed greater incorporation of TFA. Biochemical analyzes showed higher PC levels, per se, and smaller functionality of mitochondrial enzymes and decrease of some antioxidant defenses ((reduced glutathione (GSH) and vitamin C (VIT C)) in the dorsal skin HVF supplemented group. After UVR exposure, the same experimental group showed higher wrinkles scores, increased reactive species (RS) generation and PC levels, which were accompanied by decrease in GSH and VIT C skin levels. In contrast, FO group showed lower wrinkles scores and skin thickening after UVR exposure, besides lower PC levels and increased of the functionality of mitochondrial enzymes. Additionally, we observed a positive correlation between the RS generation-UVR induced and skin thickness, wrinkles and PC levels, while a negative correlation between the RS generation-UVR induced and functionality of mitochondrial enzymes, and between PC levels and GSH, SOD and VIT C.Animals of the second generation offspring (experiment 3) supplemented with FO showed higher n-3 FA incorporation and lower n-6/n-3 ratio in the dorsal skin, while TFA were incorporated only in HVF group. The latter experimental group showed biochemical changes per se: high RS generation, lower functionality of mitochondrial enzymes and increased Na+K+-ATPase activity. UVR exposure increased skin wrinkling andRS generation, besides reduced functionality of mitochondrial enzymes and GSH levels in HFV group. FO groupUVR exposure showed reduced skin thickness and PC levels, besides increase CAT activity and the preservation of Na+K+-ATPase activity. Whereas the n-3 PUFA compete with n-6 PUFA for desaturases and elongases activities, which originate from long chain n-3 or n-6 PUFA, respectively, which are incorporated into the cell membranesphospholipids.Such incorporation allows the cyclooxygenase-2 (COX-2) activity over them, originating active metabolites of the series 3 (prostaglandins (PG) and thromboxanes (TX)) or series 2 (PG and TX series 2), respectively. Series 3 metabolites are less pro-inflammatory than those of series 2, which may partly explain our findings. Moreover, to date, no study has shown the metabolites generation of AGT, even their influence on inflammation and pro-oxidant in cell membranes. How TFA have been reported to inhibit the desaturases activity, we suggest that the presence of AGT in the membranes may be inhibiting the n-3 PUFA incorporation and, thus, reduce the metabolites generation, which are known to be beneficial. Taken together, the data presented in this thesis suggest that healthy eating habits that include reduced intake of foods rich in AGT and the inclusion of n-3 PUFA, accompanied by care front sun exposure can contribute to the prevention of skin diseases and skin diseases associated with UV exposure. / Os ácidos graxos (AG) provenientes da dieta são fundamentais para a estrutura e função dos fosfolipídeos das membranas celulares, nas quais os AG poliinsaturados (AGPI) de cadeia longa aumentam a sua fluidez, enquanto os AG trans (AGT) a tornam mais rígida. Nos últimos anos, a diminuição da camada de ozônio tem aumentado a exposição humana à radiação ultravioleta (RUV), causando consequências deletérias sobre a homeostase cutânea. Por outro lado, os hábitos de vida e os padrões alimentares, especialmente em países ocidentais, tem apresentado um consumo crescente de alimentos processados ricos em AGT, cujas consequências cutâneas ainda não apresentam validação científica. Considerando que a saúde da pele está parcialmente relacionada aos lipídios que a compõem, este estudo foi desenvolvido para avaliar a influência da suplementação de diferentes óleos ou gordura em diferentes períodos da vida de roedores sobre os danos oxidativos induzidos pela exposição aguda e crônica à RUV. Camundongos Swiss machos recém desmamados foram diariamente suplementados (3g/kg; p.o.) com óleo de soja (rico em AGPI n-6) (grupo controle), óleo de peixe (rico em AGPI n-3) ou gordura vegetal hidrogenada (GVH; rica em AGT) até 90 dias de idade, quando a pele da região dorsal foi agudamente exposta à RUV. A suplementação com óleo de peixe foi relacionada à incorporação de AGPI n-3 no tecido cutâneo dos camundongos, enquanto os grupos suplementados com óleo de soja e GVH apresentaram incorporação de AGPI n-6 e AGT, respectivamente. Tais incorporações exerceram influências sobre o desenvolvimento de danos oxidativos induzidos pela RUV na pele dos camundongos, de modo que o grupo GVH mostrou maiores níveis de peroxidação lipídica e carbonilação protéica, acompanhados de maior espessamento da pele (edema), menor atividade da catalase (CAT) e viabilidade celular. Enquanto o óleo de soja foi associado a uma prevenção parcial dos danos observados no grupo GVH, a suplementação com óleo de peixe preveniu os danos oxidativos cutâneos. Sequencialmente, o segundo e terceiro protocolos experimentais foram desenvolvidos com a 1ª e a 2ª gerações de ratas adultas nascidas sob a suplementação diária dos mesmos óleos utilizados no experimento 1 (óleo de soja, óleo de peixe e GVH) e, aos 90 dias de idade, parte de cada grupo experimental foi exposto à RUV 3x/ semana, durante 12 semanas. Animais de 1ª geração (experimento 2) tratados com óleo de peixe apresentaram maior incorporação de n-3 FA e menor razão n-6/n-3 na pele dorsal, enquanto o grupo GVH mostrou maior incorporação de AGT. Análises bioquímicas mostraram um aumento dos níveis de proteína carbonil (PC), per se, menor funcionalidade das enzimas mitocondriais e diminuição de algumas defesas antioxidantes (glutationa reduzida (GSH) e vitamina C (VIT C)) na pele dorsal do grupo suplementado com GVH. Após exposição à RUV, este mesmo grupo experimental apresentou maior escore de rugas, maior geração de espécies reativas (ER) e níveis de PC, os quais foram acompanhados de uma diminuição dos níveis de GSH e de VIT C na pele dorsal. Contrariamente, o grupo óleo de peixe mostrou menor escore de rugas e espessamento da pele após exposição à RUV, além de apresentar menores níveis de PC e maior funcionalidade das enzimas mitocondriais. Adicionalmente, observou-se uma correlação positiva entre a geração de ER induzida pela RUV e a espessura da pele, rugas e PC, enquanto uma correlação negativa entre a geração de ER induzidas pela RUV e a funcionalidade das enzimas mitocondriais, e entre os níveis de PC e GSH, SOD e VIT C. Animais de 2ª geração (experimento 3) tratados com óleo de peixe apresentaram maior incorporação AG n-3 e menor razão n-6/n-3 na pele dorsal, enquanto que os AGT foram incorporados apenas no grupo GVH. Este último grupo experimental apresentou alterações bioquímicas per se: maior geração de ER, menor funcionalidade das enzimas mitocondriais e maior atividade da Na+K+ATPase. A exposição do grupo GVH à RUV aumentou a rugosidade da pele, aumentou a geração de ER e reduziu a funcionalidade das enzimas mitocondriais, além de diminuir os níveis de GSH. No grupo óleo de peixe, a exposição à RUV foi associada à menor espessura da pele e à redução dos níveis de PC, além do aumento da atividade da CAT e da preservação da atividade da Na+K+ATPase. Os AGPI n-3 competem com AGPI n-6 pela atividade das elongases e dessaturases, as quais originam AGPI de cadeia longa n-3 ou n-6, respectivamente, que são incorporados aos fosfolipídeos das membranas celulares. Tal incorporação permite a atividade da ciclooxigenase-2 (COX-2) sobre os mesmos, originando metabólitos ativos da série 3 (prostaglandinas (PG) e tromboxanos (TX) da série 3) ou da série 6 (PG e TX da série 2), respectivamente. Os metabólitos da série 3 são menos pró-inflamatórios que aqueles da série 2, o que pode em parte explicar nossos achados. Além disto, até o momento, nenhum estudo mostrou a geração de metabólitos de AGT, nem mesmo sua influência sobre o processo inflamatório e pró-oxidante nas membranas celulares. Como os AGT têm sido descritos por inibir a atividade das dessaturases, nós sugerimos que a presença de AGT nas membranas pode estar inibindo a incorporação de AGPI n-3 e, dessa maneira, reduzir a geração de seus metabólitos, os quais são reconhecidamente benéficos. Tomados em conjunto, os dados apresentados nesta tese sugerem que hábitos alimentares saudáveis, que inclui uma ingesta reduzida de alimentos ricos em AGT e a inclusão de AGPI n-3, acompanhado de cuidados frente à exposição solar, podem contribuir para a prevenção de afecções cutâneas e doenças de pele associadas à exposição UV.