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京都大学 / 新制・課程博士 / 博士(農学) / 甲第23253号 / 農博第2460号 / 新制||農||1085(附属図書館) / 学位論文||R3||N5343(農学部図書室) / 京都大学大学院農学研究科応用生命科学専攻 / (主査)教授 小川 順, 教授 阪井 康能, 教授 栗原 達夫 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

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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.

No / Background Oral administration of the omega-3 fatty acid eicosapentaenoic acid (EPA), as the free fatty acid (FFA), leads to EPA incorporation into, and reduced growth of, experimental colorectal cancer liver metastases (CRCLM). Design: We performed a Phase II double-blind, randomised, placebo-controlled trial of EPA-FFA 2 g daily in patients undergoing liver resection surgery for CRCLM. The patients took EPA-FFA (n=43) or placebo (n=45) prior to surgery. The primary end-point was the CRCLM Ki67 proliferation index (PI). Secondary end-points included safety and tolerability of EPA-FFA, tumour fatty acid content and CD31-positive vascularity. We also analysed overall survival (OS) and disease-free survival (DFS). Results The median (range) duration of EPA-FFA treatment was 30 (12–65) days. Treatment groups were well matched with no significant difference in disease burden at surgery or preoperative chemotherapy. EPA-FFA treatment was well tolerated with no excess of postoperative complications. Tumour tissue from EPA-FFA-treated patients demonstrated a 40% increase in EPA content (p=0.0008), no difference in Ki67 PI, but reduced vascularity in ‘EPA-naïve’ individuals (p=0.075). EPA-FFA also demonstrated antiangiogenic activity in vitro. In the first 18 months after CRCLM resection, EPA-FFA-treated individuals obtained OS benefit compared with placebo, although early CRC recurrence rates were similar. Conclusions EPA-FFA therapy is safe and well tolerated in patients with advanced CRC undergoing liver surgery. EPA-FFA may have antiangiogenic properties. Remarkably, limited preoperative treatment may provide postoperative OS benefit. Phase III clinical evaluation of prolonged EPA-FFA treatment in CRCLM patients is warranted. Trial Identifier: ClinicalTrials.gov NCT01070355. / The Cancer Research UK Clinical Trials Awards and Advisory Committee approved the Trial. PML and ADR were supported by Department of Health/Cancer Research UK Yorkshire Experimental Cancer Medicine Centre funding. The Trial was adopted by the UKCRN Clinical Trials Portfolio (UKCRN ID 8946) allowing West Yorkshire Comprehensive Local Research Network funding of Pharmacy costs. SLA Pharma AG funded some of the experimental work and provided EPA-FFA and placebo. SLA Pharma AG played no role in the design or execution of the Trial. Laboratory costs were also supported by the Leeds Teaching Hospitals Charitable Foundation (Rays of Hope).

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...