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1
Taylor, George. "Fatty acid metabolism in cyanobacteria." Thesis, University of Exeter, 2012. http://hdl.handle.net/10871/9363.
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With crude oil demand rising and supplies being depleted, alternative energy, specifically biofuels, are of intense scientific interest. Current plant crop based biofuels suffer from several problems, most importantly the use of land needed for food. Cyanobacteria offer a solution to this problem as they do not compete with land for food and produce hydrocarbons that can be used as biofuels. Upon examination of metabolic pathways competing with hydrocarbon synthesis, it appeared that cyanobacteria lacked the major fatty acid degradative metabolic pathway β-oxidation, generally thought to be a universally occurring pathway. Lack of this pathway in cyanobacteria was confirmed by employing a range of analytical techniques. Bioinformatic analysis suggested that potential enzymes with β-oxidation activity were involved in other metabolic pathways. A sensitive assay was set up to detect acyl- CoAs, the substrates of β-oxidation, using liquid chromatography triple quadrupole mass spectrometry. None could be detected in cyanobacteria. No enzymatic activity from the rate-limiting acyl-CoA dehydrogenase/oxidase could be detected in cyanobacterial extracts. It was found that radiolabeled fatty acids fed to cyanobacteria were utilised for lipid membranes as opposed to being converted to CO2 by respiration or into other compounds by the TCA cycle. An element of the β-oxidation pathway, E. coli acyl-CoA synthetase was ectopically expressed in a strain of cyanobacteria and implications of the introduction of acyl-CoA synthesis were assessed. Finally, the regulation of the fatty acid biosynthetic pathway was investigated. It was determined that under conditions of excess fatty acid, the transcription of acetyl-CoA carboxylase and enoyl-ACP reductase was repressed and acyl-ACP synthetase involved in fatty acid recycling was induced. These results were discussed in relation to fatty acid oxidation and hydrocarbon biosynthesis in other organisms.
2
Rose, Philip. "Indices of fatty acid metabolism." Thesis, Sheffield Hallam University, 1992. http://shura.shu.ac.uk/20296/.
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During the fed state energy requirements are met by glycolysis of carbohydrates. When the stores of carbohydrates are diminished, for example during prolonged fasting, metabolism switches to that of fatty acids. Fatty acids are broken down by fi-oxidation within the mitochondrial matrix. Prolonged fasting results in the production of ketone bodies. These can also be used as an energy source by the brain. In defects of fatty acid metabolism where individual steps are inhibited or blocked, such as medium chain acyl-CoA dehydrogenase deficiency, an abnormal accumulation of the metabolites that lead up to the block, or their breakdown products, is often seen. Non-compensatory levels of metabolites following the site of the defect also occur. In the fed state, when flux through the defective fatty acid pathway is minimal, metabolic profiles can appear completely normal. It is therefore often necessary to induce metabolic stress before a full laboratory investigation can proceed. Interpretation of individual metabolite quantitations can often be difficult and a variation of 'normal values' according to metabolic state can lead to misinterpretation. Comparison between the concentrations of related metabolites along the fatty acid metabolic pathway may diminish the need for exact knowledge of the metabolic state and by correlation plotting could clearly identify abnormal relationships. This thesis describes an investigation into the efficacy of paired metabolite correlation plots in preliminary detection of defects in fatty acid metabolism. In certain inborn errors of fatty acid metabolism where the fi-oxidation cycle is affected, abnormal urine metabolite patterns have been used as diagnostic markers. Similar patterns have been reported in the urine of healthy newborns and termed generalised neonatal dicarboxylic aciduria177. This report documents an investigation of the connections between generalised neonatal dicarboxylic aciduria and a number of overlying factors (vis type of feed, gender, sibling history of sudden infant death syndrome and urine carnitine levels). Also discussed is the development of two laboratory assays. A radio-enzymatic method was developed and used to determine the levels of total, free and acyl carnitine in urine or blood. Suberyl, hexanoyl, and phenylpropionyl glycine in urine can be quantitated by use of stable isotope internal standards and gas chromatography / electron impact mode mass spectrometry. Synthesis and calibration of such internal standards is described. Finally, methods used to culture and store skin fibroblasts from biopsy samples are included as an appendix. These fibroblasts can then be used in various diagnostic tests such as carbon dioxide release and electron transfer flavoprotein enzyme analysis. The costs encountered during tissue culture could be avoided by medium term storage of the biopsy material prior to culture to await sufficient clinical evidence to merit such analyses. Preliminary results of extended cryogenic storage and viability of recovered specimens are also included.
3
Cryle, Max Julian. "Fatty acid metabolism by cytochromes P450 /." [St. Lucia, Qld.], 2006. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19452.pdf.
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Lippmeier, James Casey. "Fatty acid metabolism of marine microalgae." Thesis, University of Hull, 2007. http://hydra.hull.ac.uk/resources/hull:7014.
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Pathways for the biosynthesis of docosahexaenoic acid (DHA) and other polyunsaturated fatty acids (PUFA) were elucidated in two heterotrophic, marine microalgae; Schizochytrium sp. and Crypthecodinium cohnii. PUFA-requiring auxotrophs of both of these algae were created and used as tools for studying PUFA biosynthetic pathways. Additionally, equilibrium radio-labeling techniques were applied to algal cultures fed 14C-fatty acids. Both organisms were found to possess two distinct pathways for PUFA biosynthesis. One pathway, mediated by classical elongases and desaturases, was incomplete in both organisms and was not capable of complementing PUFA auxotrophic phenotypes or of producing PUFA de novo, but could produce DHA from simpler PUFA precursors. The second PUFA pathway in each organism was desaturase and elongase independent. In C. cohnii, this pathway was distinguished by a capacity to produce DHA from acetate, in a manner similar to that of Schizochytrium which was shown to employ a polyketide synthase (PKS) complex for primary DHA biosynthesis. Additionally, genes of the Schizochytrium PUFA-PKS were successfully expressed in transgenic yeast, which produced DHA. Candidates for genes encoding C. cohnii PUFA-PKS components and other genes of C. cohnii PUFA biosynthesis were identified and discussed.
5
Brolinson, Annelie. "Regulation of Elovl and fatty acid metabolism." Doctoral thesis, Stockholm : Wenner-Gren Institute for Experimental Biology, Stockholm university : Stockholm University Library [distributör], 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-8469.
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Baker, Genevieve Elizabeth. "Molecular insights into bacterial fatty acid metabolism." Thesis, University of Bristol, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.715811.
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Price, Claire Louise. "Candida CYP52 : alkane and fatty acid metabolism." Thesis, Swansea University, 2012. https://cronfa.swan.ac.uk/Record/cronfa42696.
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Cytochromes P450 are a superfamily of haem-thiolate proteins found in all kingdoms of life. To date 11294 enzymes have been identified and have been shown to be involved in the metabolism of a wide variety of substrates, including hydrocarbons and xenobiotics. In yeast and fungi the hydroxylation of alkanes is associated with a family of cytochromes P450 enzymes known as CYP52s. These enzymes are involved in the terminal hydroxylation of long-chain alkanes resulting in the production of alcohols, which can be further converted to form fatty acids and diacids. In vivo such hydrocarbons can be subjected to beta-oxidation for use in growth. Alternatively, the products formed by CYP52 catalysed hydroxylation in vitro can be used in biotechnological applications. They can be used as platform chemicals in the production of a number of industrial products, including plastics, fragrances and antibiotics. The p-oxidation of fatty acids has been less well documented for Candida albicans than for other Candida species, therefore it was the aim of this study to investigate a) did cytochromes P450 exist in C. albicans that could possibly fulfil this function and b) to definitively assign function to a single cytochrome P450. Using a bioinformatic approach, five putative CYP52s were identified in C. albicans. Of these CYP52s, Alk1 was shown to have the greatest homology to the archetypal alkane-assimilating CYP52, CYP52A3 from C. maltosa. ALK1 heterologous gene expression in the brewer's yeast Saccharomyces cerevisiae allowed growth on hexadecane (C16:0) as the sole carbon source. This showed for the first time that Alk1 is involved in the hydroxylation of long-chain alkanes as normally S. cerevisiae is unable to utilise alkanes for growth. This study has also shown that Alk1 is able to interact with sterol substrates suggesting a possible role for CYP52s in sterol metabolism, which was previously unknown.
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Batugedara, Hashini Maneesha. "Fatty acid metabolism in Saccharomyces cerevisiae and effects of fatty acid metabolites on neutrophil function." Thesis, California State University, Long Beach, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=1526893.
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<p> In the presence of arachidonic acid (AA), <i>Saccharomyces cerevisiae </i> produces prostaglandin E<sub>2</sub> (PGE<sub>2</sub>). <i> S. cerevisiae</i> and its metabolites may be consumed in products manufactured using the yeast (e.g. beer). Neutrophils are immune cells present in the gastrointestinal (GI) tract during inflammation. As a lipid-signaling molecule, PGE<sub>2</sub> can potentially modify neutrophil functions and exacerbate pre-existing inflammation. As neutrophil migration is a hallmark of inflammation, we investigated the impact of PGE<sub>2</sub> on neutrophil chemotaxis. Chemotaxis assays were performed on neutrophils isolated from human whole blood using the chemotactic agents f-Met-Leu-Phe (fMLP) or interleukin-8 (IL-8). Neutrophil chemotaxis was concentration dependent as it was enhanced 3.5-fold at low concentrations of PGE<sub>2</sub> (0.1 nM-10 nM) and reduced 3.0-fold at higher concentrations of PGE<sub>2</sub> (100 nM).</p><p> The biochemical pathway utilized by <i>S. cerevisiae</i> to produce PGE<sub>2</sub> is unknown. Identifying enzymes that metabolize AA may direct approaches to reduce the impact that yeast PGE<sub>2</sub> may have on neutrophils. <i>S. cerevisiae</i> does not have genes homologous to those involved in mammalian AA metabolism. We employed RNAseq transcriptome sequencing to study the lipid biosynthetic pathway in <i>S. cerevisiae </i> and observed 1248 genes upregulated in yeast that were cultured in the presence of AA relative to yeast that were cultured without AA. Notably, genes that mediate beta-oxidation of fatty acids (<i>Pot1, Pox1, Faa1 and Faa2</i>) were upregulated up to 2.3-fold.</p><p> The results demonstrate that low concentrations of PGE<sub>2</sub> enhance neutrophil chemotaxis that is mediated by fMLP or IL-8, suggesting that PGE<sub> 2</sub> may aid in recruiting neutrophils from regions that are distant to a site of inflammation. Once a higher concentration of PGE<sub>2</sub> is encountered by neutrophils, neutrophils may halt their migration and engage effector functions such as phagocytosis and superoxide production. Increased expression of genes involved with fatty acid metabolism points to enzymes that may utilize AA to produce PGE<sub>2</sub> in <i>S. cerevisiae</i>. Experiments testing PGE<sub>2</sub> levels in knock-out strains of yeast will identify genes involved in PGE<sub>2</sub> production. Results of this study have implications to reduce potential off-target effects caused by yeast PGE<sub> 2</sub> in consumables.</p>
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Mardy, Jennifer Kai. "Fatty acid metabolism in isolated perfused mouse hearts." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/MQ64969.pdf.
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Masterson, Christine. "Carnitine and fatty acid metabolism in higher plants." Thesis, University of Newcastle Upon Tyne, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.254030.
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Emmision, Neil. "Aspects of fatty acid metabolism in cultured hepatocytes." Thesis, University of Newcastle Upon Tyne, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287298.
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Maher, Michael. "An epigenetic approach to fatty acid metabolism in haematological malignancies." Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/673704.
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The role of fatty acids to overcome stress and contribute to disease progression is becoming increasingly evident in haematological diseases. Further, epigenetic factors play an important role in the aetiology of myelodysplastic syndromes (MDS) and the transformation to secondary acute myeloid leukaemia (sAML). To investigate this in the MDS/sAML cell line, SKK-1, we employed a shRNA knockdown screen to target 912 epigenetic regulators. We then coupled this loss-of-function approach to a fatty acid metabolism-based assay with which we were able to cell-sort the SKK-1 cells based on the fatty acid uptake. Here I describe the methodology of this epigenetics-metabolism approach and our efforts to validate candidate hits from the screen that were predicted to be modulators of fatty acid uptake. Following testing using single gene knockdowns of the top genes from the screen, we were not able to identify epigenetic regulators that significantly alter fatty acid uptake. In parallel, we characterised metabolic and genetic parameters of triple-sorted low (TS LOW) and high (TS HIGH) fatty acid uptake sub- populations. However, during the course of the study, we discovered latent contamination by another myeloid cell line, U-937, in our SKK-1 parental cells and TS LOW and TS HIGH sub-populations. Therefore, we interpreted results from the characterisation study with the knowledge that we had mixed cellular populations. I describe the steps we took to first identify the cell line and then our further characterisation of single cell clones of TS LOW and TS HIGH. Interestingly, we observed distinct cytogenetic profiles between single clones of TS LOW and TS HIGH, namely trisomy 8, which is a highly relevant chromosomal aberration in myeloid malignancies. Overall, this study provides a novel approach to investigate epigenetic and metabolic interactions in blood malignancies. We also find metabolically distinct sub-populations that differ by a disease-relevant karyotype.
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Bruce, Jennifer S. "Dietary saturated fatty acids and lipoprotein metabolism in the hamster." Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.319647.
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Field, Helen Patricia. "The interrelationship of zinc and essential fatty acid metabolism." Thesis, University of Leeds, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.236407.
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Madrigal, Jorge Fonseca. "Fatty acid metabolism in isolated enterocytes from salmonid fish." Thesis, University of Stirling, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.440781.
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Kilaru, Aruna. "Fatty Acid Ethanolamide Metabolism Influences Growth and Stress Responses." Digital Commons @ East Tennessee State University, 2014. https://dc.etsu.edu/etsu-works/4773.
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Brindle, N. P. J. "Comparative studies on the regulation of hepatic fatty acid metabolism." Thesis, University of Manchester, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.374534.
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Neijat, Mohamed. "Omega-3 fatty acid enrichment of chicken eggs: Regulation of long chain polyunsaturated fatty acid metabolism in laying hens." Poultry Science, 2014. http://hdl.handle.net/1993/32076.
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Eggs enriched with omega-3 polyunsaturated fatty acids (PUFA), particularly the longer chain PUFA (LCPUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) can boost human consumption of these fatty acids implicated in human health. Alpha-linolenic acid (ALA) from plant seeds/oils, primarily serve as the source of omega-3 PUFA for hens, however, the scarcity of ALA-rich plants and the limited conversion of ALA to LCPUFA are challenges for egg enrichment. Two major experiments were conducted to determine potential factors regulating egg enrichment of omega-3 LCPUFA based on detailed assessment of PUFA profiles in different lipid pools of hen tissues. In experiment 1, supplementation of graded levels of hempseed products, provided ~ 0.1 to 1.3% of ALA in the diets. Experiment 2, investigated dietary supplementation of flaxseed oil (ALA-rich) and algal DHA (preformed LCPUFA), each providing similar graded levels of total omega-3 PUFA. Both ALA-containing models demonstrated a plateau in DHA enrichment of eggs at higher ALA intakes. ALA-containing diets led to high concentrations of ALA in the triacylglycerol (TAG) fraction of eggs and plasma, and the adipose tissue of flaxseed oil-fed hens. In total phospholipid (PL), particularly the phosphatidylethanolamine (PE), the levels of EPA and ALA in the yolk were linearly associated with those in the liver. In all tissues, DHA dominated the PE pool, exhibiting a plateau with a strong inverse correlation to the ratio of ALA to EPA in the liver, suggesting limited ALA availability for egg DHA enrichment. The use of algal DHA should therefore permit further accumulation of DHA in the total PL and TAG fractions of yolk. However, enrichment via preformed DHA (at 3.36% algal product) was also limited by hepatic PL resulting in more DHA and EPA being shunted to the adipose TAG, concurrent with elevated hepatic acyl-CoA synthetase (ACSL1) expression. As a function of total omega-3 PUFA intakes (regardless of source), similar levels of stearidonic acid (SDA) and particularly EPA accumulated in liver PE. Therefore, hepatic PL regulation, possibly aimed at maintaining EPA level, may potentially be limiting the amount of ALA accumulation in the same pool, hence limiting the endogenous synthesis of DHA and subsequent enrichment in eggs.<br>February 2017
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Farrell, Emma K. "Biosynthesis of fatty acid amides." Scholar Commons, 2010. http://scholarcommons.usf.edu/etd/1629.
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Primary fatty acid amides (PFAMs) and N-acylglycines (NAGs) are important signaling molecules in the mammalian nervous system, binding to many drug receptors and demonstrating control over sleep, locomotor activity, angiogenesis, vasodilatation, gap junction communication, and many other processes. Oleamide is the best-studied of the PFAMs, while the in vivo activity of the others is largely unstudied. Even less is known about the NAGs, as their discovery as novel compounds is much more recent due to low endogenous levels. Herein is described extraction and quantification techniques for PFAMs and NAGs in cultured cells and media using solvent extraction combined with solid phase extraction (PFAM) or thin layer chromatography (NAG), followed by gas chromatography-mass spectroscopy to isolate and quantify these lipid metabolites.
The assays were used to examine the endogenous amounts of a panel of PFAMs as well as the conversion of corresponding free fatty acids (FFAs) to PFAMs over time in several cell lines. The cell lines demonstrated the ability to convert all FFAs, including a non-natural FFA, and an ethanolamine to the corresponding PFAM. Different patterns of relative amounts of endogenous and FFA-derived PFAMs were observed in the cell lines tested. Essential to identifying therapeutic targets for the many disorders associated with PFAM signaling is understanding the mechanism(s) of PFAM and NAG biosynthesis. Enzyme expression studies were conducted to determine potential metabolic enzymes in the model cell lines in an attempt to understand the mechanism(s) of PFAM biosynthesis. It was found that two of the cell lines which show distinct metabolisms of PFAMs also demonstrate unique enzyme expression patterns, and candidate enzymes proposed to perform PFAM and NAG metabolism are described.
RNAi knockdown studies revealed further information about the metabolism of PFAMs and calls into question the recently proposed involvement of cytochrome c. Isotopic labeling studies showed there are two pathways for PFAM formation. A novel enzyme is likely to be involved in formation of NAGs from acyl-CoA intermediates.
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Takeuchi, Michiki. "Biochemical and applied studies on unsaturated fatty acid metabolisms in lactic acid bacteria." Kyoto University, 2015. http://hdl.handle.net/2433/199370.
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Kyoto University (京都大学)<br>0048<br>新制・課程博士<br>博士(農学)<br>甲第19046号<br>農博第2124号<br>新制||農||1032(附属図書館)<br>学位論文||H27||N4928(農学部図書室)<br>31997<br>京都大学大学院農学研究科応用生命科学専攻<br>(主査)教授 小川 順, 教授 加納 健司, 教授 植田 充美<br>学位規則第4条第1項該当
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Portolesi, Roxanne, and roxanne portolesi@flinders edu au. "Fatty acid metabolism in HepG2 cells: Limitations in the accumulation of docosahexaenoic acid in cell membranes." Flinders University. Medicine, 2007. http://catalogue.flinders.edu.au./local/adt/public/adt-SFU20070802.103146.
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The current dietary recommendations for optimal health are designed to increase our intake of two bioactive omega-3 (n-3) fatty acids, eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), abundant naturally in fatty fish such as salmon. Health authorities recommend that the general population consume two to three fatty fish meals per week (1) for optimal health and for the prevention of cardiovascular disease. However, some modern Western societies consume only modest amounts of fish and seafood (2;3). Land based vegetable oils may provide an alternative to meet these needs. Linseed and canola oils are rich in alpha-linolenic acid (ALA, 18:3n-3) (4). ALA can be converted endogenously to EPA and DHA and suggests that increasing the dietary intake of ALA may increase the conversion and accumulation of DHA in tissues and plasma. However, elevated dietary intakes of ALA in animals and humans results in an increased level of EPA in tissues yet there is little or no change in the level of DHA (5-7). The current consensus is that the synthesis of DHA from ALA in humans is limited yet the mechanisms involved in regulating the accumulation of DHA in tissues are poorly understood.
The reputed rate-limiting enzyme in the conversion of fatty acids is delta 6 desaturase (D6D). ALA is a substrate for D6D and undergoes a series of desaturation and elongation reactions to yield n-3 long chain polyunsaturated fatty acids (LCPUFA). The final step in the synthesis of DHA from ALA involves translocation of its immediate fatty acid precursor, 24:6n-3 from the endoplasmic reticulum to the peroxisome to be partially beta-oxidised to yield DHA. The involvement of multiple enzymes in the desaturation-elongation pathway, and the integration of other pathways, such as phospholipid biosynthesis, suggests there are various steps that may regulate the accumulation of DHA in cell membranes. This thesis aimed to examine the possible regulatory steps in the conversion of fatty acids to LCPUFA, particularly in the synthesis of DHA from n-3 fatty acid precursors.
The human hepatoma cell line, HepG2, was used as an in vitro cell system to examine the accumulation of individual fatty acids and their metabolites in isolation from other competing fatty acid substrates. The accumulation of linoleic acid (LA, 18:2n-6) and ALA in HepG2 cell phospholipids following supplementation with increasing concentrations of each respective fatty acid correlated with that described in vivo, as was the accumulation of their conversion products. The accumulation of DHA in cells supplemented with ALA reached a plateau at concentrations above 5 micro g/ml and paralleled the accumulation of 24:6n-3 in cell phospholipids, suggesting that the delta 6 desaturation of 24:6n-3 was prevented by increasing concentrations of ALA, thereby limiting the accumulation of DHA. The accumulation of DHA in cells supplemented with eicosapentaenoic acid (EPA, 20:5n-3) or docosapentaenoic acid (DPA, 22:5n-3) was significantly greater than the level of DHA that accumulated in cells supplemented with ALA. However, regardless of substrate, the level of DHA in cell membranes reached a plateau at substrate concentrations above 5 micro g/ml.
This thesis further aimed to examine the effect of fatty acid supplementation on the mRNA expression of D6D in HepG2 cells. The expression and activity of D6D mRNA is subject to nutritional and hormonal regulation. The mRNA expression of D6D in HepG2 cells following supplementation with oleic acid (OA, 18:1n-9), LA, ALA, arachidonic acid (AA, 20:4n-6) or EPA was examined by real time RT PCR. The expression of D6D mRNA was reduced by up to 50% in cells supplemented with OA, LA, ALA , AA or EPA compared with control cells and suggests that fatty acids modulate the expression of the key enzyme involved in the conversion of fatty acids.
The effect of fatty acid co-supplementation on the fatty acid composition of HepG2 cell phospholipids was also examined in an attempt to gain insights into the role of D6D and the enzymes involved in peroxisomal beta-oxidation on the accumulation of DHA from n-3 fatty acid precursors. The reduction in the accumulation of DHA in cells co-supplemented with DPA and docosatetraenoic acid (DTA, 22:4n-6) was greater than in cells co-supplemented with DPA and LA, suggesting that peroxisomal beta-oxidation may have a greater role in determining the accumulation of DHA from DPA than the activity of D6D. Further investigation should be directed towards understanding the role that peroxisomal beta-oxidation may play in the synthesis of DHA from precursor fatty acids.
The fatty acid composition of cell membranes in vivo is a result of several physiological processes including dietary intake, phospholipids biosynthesis and fatty acid conversion as well as catabolic processes. This thesis demonstrates that a greater understanding of the regulation of the conversion of fatty acids will help to define dietary approaches that enhance the synthesis of n-3 LCPUFA from n-3 fatty acid precursors to lead to improved outcomes for health.
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Bhura-Bandali, Farah. "The cystic fibrosis transmembrane conductance regulator in essential fatty acid metabolism." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq22572.pdf.
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Corpeleijn, Eva. "Fatty acid metabolism, impaired glucose tolerance and the effects of lifestyle." [Maastricht] : Maastricht : [Maastricht University] ; University Library, Universiteit Maastricht [host], 2006. http://arno.unimaas.nl/show.cgi?fid=10536.
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Khan, Nusrat Sultana. "Studies on membrane fatty acid metabolism and transduction mechanisms in schizophrenia." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313663.
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Klizaite, Kristina [Verfasser]. "Medium-chain fatty acid metabolism in hepatocytes and adipocytes / Kristina Klizaite." Bonn : Universitäts- und Landesbibliothek Bonn, 2017. http://d-nb.info/115995514X/34.
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Taylor, Rebecca Clare. "Mycobacterial fatty acid metabolism : identification of novel drug targets and chemotherapeutics." Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/3192/.
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Tuberculosis has been a deadly human pathogen for thousands of years and is as prevalent and lethal now as it was in the pre-antimicrobials era. With new challenges continually being presented in the form of multidrug resistant strains evolving and the implications of the HIV epidemic, it is imperative that every effort is made to understand the causative agent, Mycobacterium tuberculosis, and develop new effective and affordable drugs to treat the disease. With this in mind, the first part of this project tests novel drugs that have been identified using different approaches. The desired targets for all the compounds were the fatty acid and mycolic acid biosynthesis systems in M. tuberculosis, Mycobacterium bovis BCG and Mycobacterium smegmatis. Some promising compounds were identified, which inhibited enzymes of the prokaryotic FAS-II system, whilst not affecting the mammalian FAS-I system. As well as identifying new drugs, it is equally important to recognise the essential genes of M. tuberculosis, which could be novel drug targets. Whilst the fatty acid biosynthesis pathway has been well studied, a lot less is known about fatty acid degradation. M. tuberculosis has an abundance of fad genes, yet it is only recently that they have started to be explored. Here, the functions and roles of the fadB genes in M. tuberculosis, M. bovis BCG and M. smegmatis have been explored. By producing purified recombinant protein and generating gene deletion mutants, it has been possible to fully characterise Mt-FadB2 and provide preliminary information regarding fadB3, fadB4 and fadB5.
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Etwebi, Zienab. "Magnesium Regulation of Glucose and Fatty Acid Metabolism in HEPG2 Cells." Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1307564164.
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Jones, Barney. "Ischaemia and efficiency in the isolated heart." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311982.
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Simoens, Christian. "Intravascular metabolism of lipid emulsions with different fatty acid pattern: influence on fatty acid profile of membrane phospholipids in target organs and cells." Doctoral thesis, Universite Libre de Bruxelles, 2011. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209776.
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Papamandjaris, Andrea A. "The effect of fatty acid chain length on energy metabolism in healthy women." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0026/NQ50233.pdf.
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Baker, Jennifer Mary. "The effect of extracellular pH on human platelet metabolism." Thesis, University of Birmingham, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368422.
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Chen, Chaw-Yuan. "Regulation, Evolution, and Properties of the ato Qperon and its Gene Products in Escherichia coli." Thesis, University of North Texas, 1993. https://digital.library.unt.edu/ark:/67531/metadc277592/.
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The regulation of short chain fatty acid metabolism has been examined. Metabolism of acetoacetate, and short chain fatty acids such as butyrate and valerate, is predicated upon the expression of genes of the ato operon. Acetoacetate induces expression of a CoA transferase (encoded by the atoDA genes) and expression of a thiolase (encoded by the atoB gene). Metabolism of saturated short chain fatty acids requires the activities of the transferase and thiolase and enzymes of 6-oxidation as well. Spontaneous mutant strains were isolated that were either constitutive or that were inducible by valerate or butyrate instead of acetoacetate.
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Teran-Garcia, Margarita de Lourdes. "Functional mapping and characterization of the responsive region required for polyunsaturated fatty acid regulation in the rat fatty acid synthase gene." Access restricted to users with UT Austin EID Full text (PDF) from UMI/Dissertation Abstracts International, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3035987.
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Furumoto, Hidehiro. "Studies on Nutraceutical Properties of Modified Fatty Acids by Autoxidation and Lactic Acid Bacterial Metabolism." Kyoto University, 2016. http://hdl.handle.net/2433/215592.
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Kyoto University (京都大学)<br>0048<br>新制・課程博士<br>博士(農学)<br>甲第19766号<br>農博第2162号<br>新制||農||1040(附属図書館)<br>学位論文||H28||N4982(農学部図書室)<br>32802<br>京都大学大学院農学研究科応用生物科学専攻<br>(主査)教授 菅原 達也, 教授 澤山 茂樹, 教授 佐藤 健司<br>学位規則第4条第1項該当
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Tunedal, Kajsa. "Mathematical modeling of fatty acid metabolism during consecutive meals and fasting : New insights into fatty acid regulation based on arterio-venous data." Thesis, Linköpings universitet, Institutionen för medicinsk teknik, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-177309.
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Obesity, type 2 diabetes, and cardiovascular diseases are major problems in today's society, causing millions of deaths every year. One of the main risk factors for these diseases is a dysregulation of the fatty acid metabolism, where the balance between release and uptake of fatty acids is disturbed. Thus, understanding how fatty acid metabolism works is of great importance in the battle against these diseases. The human fatty acid release and uptake can be unraveled by measuring the difference in metabolite concentrations between an artery before the adipose tissue and a vein draining the tissue. Such measurements are called arterio-venous. However, due to the complexity of the fatty acid mechanisms, the resulting measurements alone are not enough to understand all of the involved reactions governing the metabolism. One analytical tool to decipher such complex mechanisms is mathematical modeling. A few mathematical models have previously used arterio-venous data of the fatty acid metabolism, but none of the previous models describe a full day including several meals and nightly fast. In this project, I combine mathematical modeling and arterio-venous data to investigate the mechanisms of fatty acid metabolism during three consecutive meals and fasting. The resulting mathematical model can explain arterio-venous data of free fatty acids, triglycerides, and glycerol. The model predictions show that re-esterification of monacylglycerides, a mechanism that has not been considered before when analyzing arterio-venous data, is of importance to be able to accurately describe the fatty acid metabolism. Additionally, the model predicts that there is a hormonal regulation during the night. Finally, it is shown that many of the previous simple calculations used to approximate metabolic reactions do not capture the desired reactions but instead calculate more complex properties, while the use of the model allows for a more detailed analysis separating all of the different reaction rates. These results give new insights into the complex mechanisms of fatty acid metabolism and provide a new tool to analyze arterio-venous data more comprehensively. In the future, this can lead to a better understanding of metabolic diseases such as obesity, type 2 diabetes, and cardiovascular diseases.
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MAXWELL, BESS DEVERE. "SERUM FREE FATTY ACID CONCENTRATION DURING POST-EXERCISE RECOVERY (INSULIN, HUNGER)." Diss., The University of Arizona, 1985. http://hdl.handle.net/10150/187956.
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In order to achieve a better understanding of the impact of exercise on the concentration of serum free fatty acids (FFA) during post-exercise recovery, the purposes of this study were: (1) to determine the relationships between exercise intensity, total exercise energy expenditure, and the concentration of serum FFA during post-exercise recovery; (2) to examine the effects of exoge- nous glucose on post-exercise serum FFA and hormones controlling the FFA response; and (3) to examine the impact of acute exercise on hunger. Untrained, 12-h fasted, college-age males performed cycle ergometer exercise at exercise intensities ranging from 29 to 59% peak ‘VO₂ for total energy expenditures ranging from 162 to 320 kcal. Blood samples, hunger ratings, and metabolic indices were collected or measured before, during, and for 3 h post-exercise. In response to exercise of approximately 300 kcal, FFA was elevated for 3 h post-exercise. The FFA response was a function of total exercise energy expenditure, rather than exercise intensity, or combined effects of these factors. The response was associated with low insulin concentration but no changes were observed in blood glucose, glucagon, growth hormone, or cortisol. Glucose ingestion and infusion studies demonstrated that possible mechanisms con- tributing to the post-exercise FFA response included decreases in FFA re-esterification, increases in triglyceride hydrolysis, and decreases in sympathetic input to adipose tissue. Exercise caused a suppression of hunger for 2 h post-exercise which was a function of the combined effects of exercise intensity and total energy expenditure. An increase in core temperature may have contributed to the anorexigenic effect of exercise. In conclusion, exercise, performed in and followed by a period of fasting caused an elevation of FFA for 3 h during post-exercise recovery. The post-exercise recovery period should be considered an important phase in the physiological impact of exercise on the storage and utilization of fat.
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Stahl, Richard J. (Richard John). "Fatty acid and glycerolipid biosynthesis in pea root plastids." Thesis, McGill University, 1990. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=22389.
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Fatty acid biosynthesis from (1-$ sp{14}$C) acetate was optimized in plastids isolated from primary root tips of 7-day-old germinating pea seeds. Fatty acid synthesis was maximum at 82.3 nmol/hr/mg protein in the presence of 200$ mu$M acetate, 0.5mM each of NADH, NADPH and CoA, 6mM each of ATP and MgCl$ sb2$, 1mM each of MnCl$ sb2$ and glycerol-3-phosphate (G3P), 15mM KHCO$ sb3$, and 0.1M Bis tris propane, pH 8.0 incubated at 35C. At the standard incubation temperature of 25C, fatty acid synthesis was linear for up to 6 hours with 80 to 120 $ mu$g/ml plastid protein. ATP and CoA were absolute requirements, whereas divalent cations, potassium bicarbonate and reduced nucelotides all improved activity by 2 to 10 fold. Mg$ sp{2+}$ and NADH were the preferred cation and nucleotide, respectively. G3P and dihydroxyacetone phosphate had little effect, and dithiothreitol and detergents generally inhibited incorporation of $ sp{14}$C-acetate into fatty acid.<br>Glycerolipid synthesis was obtained from $ sp{14}$C-acetate, (U-$ sp{14}$C) G3P and (U-$ sp{14}$C) glycerol at relative rates of 3.7:1.0:0.1, respectively. (Abstract shortened by UMI.)
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Morgan, Eric E. "The Cardiac Fatty Acid Metabolic Pathway in Heart Failure." Case Western Reserve University School of Graduate Studies / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=case1138394643.
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Waterman, Ian J. "Role of placental lipase in feto-placental fatty acid uptake and metabolism." Thesis, Robert Gordon University, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298317.
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Guiu, Jurado Esther. "Deregulation of fatty acid metabolism in the adipose tissue of obese women." Doctoral thesis, Universitat Rovira i Virgili, 2016. http://hdl.handle.net/10803/386542.
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L'obesitat augmenta el risc i empitjora el pronòstic de moltes malalties. No obstant això, l'obesitat en sí no condueix necessàriament a aquestes comorbiditats. La disfunció del teixit adipós, l'acumulació de greix ectòpic i la desregulació del metabolisme dels àcids grassos (AG) en l’adipòcit semblen jugar un paper important en la determinació del risc d'un individu de desenvolupar comorbiditats. És per això que seria de gran interès estudiar els mecanismes relacionats amb la desregulació del metabolisme dels AG en el teixit adipós durant el desenvolupament de l'obesitat per tal de millorar el coneixement de la fisiopatologia de l'obesitat. Per tant, es va proposar la hipòtesi que l'expressió de gens i factors de transcripció implicats en la regulació del metabolisme d'AG podria estar alterada en pacients obesos, i que aquesta alteració podria estar relacionada amb la disfunció del teixit adipós. En conseqüència, l'objectiu principal va ser investigar les vies relacionades amb el metabolisme dels AG en el teixit adipós subcutani (SBC) i visceral (VSC) de dones obeses. Amb aquesta finalitat, es va avaluar l'expressió de gens clau involucrats en el metabolisme dels AG en mostres de SBC i VSC en una extensa cohort de dones obeses (145 obeses mòrbides (IMC>40 kg/m2) i 55 obeses moderades (IMC 30-38 kg/m2)) i en 35 dones controls (IMC<25 kg/m2) mitjançant RT-qPCR i Western Blot. La troballa més rellevant va ser que l'expressió dels principals gens involucrats en la lipogènesi va ser significativament menor en les dones obeses comparat amb les controls en el teixit SBC, mentre que en el VSC l'expressió va ser similar. A més, els nostres resultats indiquen que, durant el desenvolupament de l'obesitat, hi ha una disminució progressiva en la lipogènesi en el SBC, suggerint que aquest teixit podria tenir un mecanisme de defensa contra l'excés d'acumulació d'AG.<br>La obesidad aumenta el riesgo y empeora el pronóstico de muchas enfermedades. Sin embargo, la obesidad en sí no conduce necesariamente a estas comorbilidades. La disfunción del tejido adiposo, la acumulación de grasa ectópica y la desregulación del metabolismo de los ácidos grasos (AG) en el adipocito parecen jugar un papel importante en la determinación del riesgo de un individuo de desarrollar comorbilidades. Es por ello que sería de gran interés estudiar los mecanismos relacionados con la desregulación del metabolismo de los AG en el tejido adiposo durante el desarrollo de la obesidad con el fin de tener un mejor conocimiento de la fisiopatología de la obesidad. Por lo tanto, se propuso la hipótesis de que la expresión de genes y factores de transcripción implicados en la regulación del metabolismo de AG podría estar alterada en pacientes obesos, y que esta alteración podría estar relacionada con la disfunción del tejido adiposo. En consecuencia, el objetivo principal fue investigar las vías relacionadas con el metabolismo de los AG en el tejido adiposo subcutáneo (SBC) y visceral (VSC) de mujeres obesas. Con ese fin, se evaluó la expresión de genes clave involucrados en el metabolismo de los AG en muestras de SBC y VSC en una extensa cohorte de obesas (145 obesas mórbidas (IMC>40 kg/m2) y 55 obesas moderadas (IMC 30-38 kg/m2)) y en 35 mujeres controles (IMC<25kg/m2) mediante RT-qPCR y Western Blot. El hallazgo más relevante fue que la expresión de los principales genes involucrados en la lipogénesis fue significativamente menor en las mujeres obesas comparado con las controles en el tejido SBC, mientras que en el VSC la expresión fue similar. Además, nuestros resultados indican que, durante el desarrollo de la obesidad, existe una disminución progresiva en la lipogénesis en el SBC, sugiriendo que este tejido podría tener un mecanismo de defensa contra el exceso de acumulación de AG.<br>Obesity significantly increases the risk and worsens the prognosis of many diseases. However, obesity itself does not necessarily lead to these comorbidities. Adipose tissue dysfunction and ectopic fat accumulation seem to play an important role in determining an individual’s risk of developing the metabolic and cardiovascular comorbidities of obesity. Likewise, deregulation of adipocyte fatty acid (FA) metabolism also contributes to the development of metabolic diseases. Based on previous data, a better understanding of the underlying mechanism of the deregulation of FA metabolism in adipose tissue during the development of obesity could be of great interest and could provide a better understanding of the physiopathology of obesity. We therefore hypothesized that in obese patients, the expression of genes and transcription factors involved in the regulation of FA metabolism could be altered; and this alteration may be related to adipose tissue dysfunction. Consequently, the main objective was to further investigate the pathways related to FA metabolism in the subcutaneous (SAT) and visceral (VAT) adipose tissue of obese women. To that end, we evaluated the expression of key genes involved in FA metabolism in SAT and VAT by RT-qPCR and Western Blot in an extensive obese cohort (145 morbidly obese (BMI>40 kg/m2) and 55 moderately obese (BMI 30-38 kg/m2) women) and 35 normal-weight women (BMI<25 kg/m2). The main finding was that the expression of the key genes involved in lipogenesis was significantly lower in the SAT depot of obese women than in those of the control, whereas in VAT had similar expression. Moreover, our results indicate that there is a progressive downregulation in lipogenesis in SAT during the development of obesity, suggesting that, in obese individuals, SAT has a defensive mechanism against an excess of FA accumulation that prevents the subcutaneous fat mass from developing further by decreasing the expression of lipogenic genes, whereas VAT may have lost this mechanism.
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Mels, Catharina Martha Cornelia. "The assessment of detoxification metabolism in fatty acid oxidation deficiencies / C.M.C. Mels." Thesis, North-West University, 2010. http://hdl.handle.net/10394/4406.
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The concept of accumulating xenobiotics within the human body as a health risk is well known. However, these compounds can also be endogenous, as in the case of inborn errors of metabolism. Biotransformation of both exogenous and endogenous toxic compounds is an important function of the liver, and the critical balance between these systems is of fundamental importance for cellular health. Fatty acid ?-oxidation deficiencies are associated with characteristic clinical symptoms as a consequence of the accumulation of specific metabolites. For these accumulated metabolites various nutrients are indispensable for optimal biotransformation and continuous accumulation of metabolites can ultimately result in the depletion of biotransformation substrates and cofactors.
In this study, a novel model (the unbalanced biotransformation metabolism model) is proposed that describes the critical balance between Phase I and Phase II biotransformation and how a disturbance in this balance will increase the oxidative stress status. The significance of this model lies within the treatment possibilities, as the assessment of biotransformation metabolism and oxidative stress status can lead to the development of nutritional treatment strategies to correct imbalances. The value of this model is illustrated by its application to a clinical case investigated.
In addition to the use of nutritional supplementation in treatment, biotransformation substrates and cofactors were also used to develop a ?substrate loading cocktail?. This cocktail ensured sufficient availability of biotransformation substrates and precursors to stimulate coenzyme A biosynthesis. The application of this ?substrate loading cocktail? in subjects with both induced and inborn errors in fatty acid oxidation demonstrated that such a novel approach is a useful tool to give new insight into these kinds of deficiencies and open the possibility for the identification of new deficiencies.
Interesting observations made in subjects originally referred for biotransformation and oxidative stress status profiles led to the first in vivo evidence of an inhibitory effect of acetylsalicylic acid on short-chain fatty acid metabolism possibly at the level of isobutyryl-CoA dehydrogenase. Since not all individuals were affected to the same degree, this observation can potentially be used to detect individuals with rate-limiting polymorphisms or mutations in the isobutyryl-CoA dehydrogenase enzyme.<br>Thesis (Ph.D. (Biochemistry))--North-West University, Potchefstroom Campus, 2011.
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Jackson, Kim Geraldine. "Acute and chronic effects of monounsaturated fatty acid intake on chylomicron metabolism." Thesis, University of Surrey, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360952.
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Intriago, Pablo. "Fatty acid metabolism in a flexibacterium and its role in crustacean nutrition." Thesis, Bangor University, 1990. https://research.bangor.ac.uk/portal/en/theses/fatty-acid-metabolism-in-a-flexibacterium-and-its-role-in-crustacean-nutrition(11232774-8084-428b-854b-8652696a0f43).html.
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The total fatty acid content of an estuarine Flexibacter trip and the relative proportion of the constituent fatty acids were affected by growth temperature, aeration and salinity. The proportion of Cl6:lw5 the main fatty acid, did not change with temperature, but was produced in higher concentrations in xhe aiMOu*t o{ shaking cultures. In contrast, the amount of both linoleic and linolenic acids varied with temperature and aeration. The concentration of Cl6:lw5 per mg of protein changed with temperature, whereas the concentrations of both polyunsaturates were relatively constant. Both the proportion and concentration of the polyunsaturates were markedly stimulated by increases in salinity, although total fatty acid per mg protein decreased with it. The highest concentration of fatty acid per mg of protein did not coincide with the highest percentage of polyunsaturated fatty acids (PUFAs), when Inp was grown in different carbon sources. Inp growing in glucose had the highest concentration of PUFAs per mg of protein. Radio labelled acetate and palmitate were differentially incorporated into the fatty acids of Inp2 a variant of Inp. Addition of cAMP inhibited the incorporation of radioactive precursors into PUFAs. In contrast the antibiotic cerulenin inhibited the incorporation of radio labelled substrate acetate and variant into C16:1. This strongly suggests that lnp2 posseses both the anaerobic and aerobic pathway for UFAs synthesis. Whilst PUFAs were absent when another variant lnp3 was grown in media with an osmotic strength close to that of seawater, PUFAs were produced when Inp3 was grown in a high osmotic strength medium. Addition of cAMP to the high osmotic strength medium prevented PUFAs synthesis. Artemia salina was grown to adulthood on diets consisting of bacteria, bacteria plus algae and algae only. Generally, there were no differences in survival between the diets. However, different diets reflected differences in the total dry weight. Addition of algae to the Inp3 diet increased PUFAs concentration per animal dry weight. It is suggested that Inp3 may be able to provide both PUFAs and exoenzymes, which assist in the digestion of algae.
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Zampelas, Antonios. "Effect of dietary fatty acid structure and composition on postprandial lipid metabolism." Thesis, University of Surrey, 1993. http://epubs.surrey.ac.uk/770401/.
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In this thesis effects of dietary fatty acid composition and of positional distribution of fatty acids in dietary TAG, on postprandial lipid and hormone responses, were investigated. A6 week fish oil supplementation period (2.7 g n-3 fatty acids per day) decreased fasting TAG and increased TC (p<0.05) and LDL-C (p<0.05) levels in normal subjects. Postprandial plasma TAG responses to a test meal were also significantly reduced following the fish oil supplementation period (area under the response curves, p<0.001). Apolipoproteins A-I and B responses did not alter in response to chronic fish oil supplementation. Type II diabetics responded differently to normal subjects to fish oil supplementation. Fasting lipid and apolipoprotein levels were not significantly altered, and the postprandial TAG response to a test meal showed a trend towards higher values following the fish oil supplementation period. In the study of effects of dietary TAG structure on postprandial lipid apolipoprotein (A-I, B), hormone (insulin, GIP) and glucose responses, no effect of test meals differing in the positional distribution of palmitic acid at the sn-2 or the sn-3 positions of the TAG molecule were seen. In a study of acute effects of dietary fatty acid composition in healthy male subjects, a fish oil test meal (40 g fish oil concentrate), significantly reduced plasma TAG postprandial responses compared with a mixed oil meal (containing 40 g of a mixture of oils high in SFA and mimicking the current U. K. dietary fat intake), p<0.05. Post-heparin LPL activity was also significantly increased 12 hours following the fish oil test meal (p<0.01). A 40 g corn oil test meal did not have any significant effect on postprandial lipid, hormone (insulin and GIP), and retinyl palmitate levels (the latter was administered with each test meal-700 I. U. /kg of body weight) compared with the other two test meals. A feeding study, using a rat model, showed that following two weeks of a fish oil diet (5%, w/w) the postprandial incorporation of [U-t4C]glucose into hepatic total lipids and TAG measured in vitro, was significantly reduced compared with rates measured in animals on a mixed oil diet (p<0.05). In the presence of the two anabolic hormones, insulin and GIP, in vitro rates of hepatic cholesterogenesis increased (p<0.05), and these effects of hormones were independent of the type of the diet fed. In addition, plasma TAG levels were significantly lower in the fish oil group compared with levels in the mixed oil and corn oil dietary groups (p<0.05), and plasma insulin levels were significantly higher in the mixed oil dietary group than in the other two groups (p<0.001).
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Ford, Tyler John. "Engineering Escherichia Coli Fatty Acid Metabolism for the Production of Biofuel Precursors." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467357.
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Medium chain fatty acids (MCFAs, 6-12 carbons) are potential precursors to biofuels
with properties similar to gasoline and diesel fuel but are not native products of Escherichia coli
fatty acid synthesis. Herein we engineer E. coli to produce, metabolize, and activate MCFAs for
their future reduction into alcohols and alkanes (potential biofuels). We develop an E. coli strain
with an octanoate (8-carbon MCFA) producing enzyme (a thioesterase), metabolic knockouts,
and the capability to inducibly degrade an essential metabolic enzyme that would otherwise
divert carbon flux away from octanoate. We show that this strain can produce octanoate at 12%
theoretical yield. To determine limitations on octanoate catabolism that could prevent its
conversion into an acyl-CoA thioester activated for later reduction into alcohols and alkanes, we
evolve E. coli to grow on octanoic acid as sole carbon source. We show that our fastest growing
evolved strain contains mutations that enhance the expression of acyl-CoA synthetase FadD. We
then directly mutate the fadD gene and screen for mutations that enhance growth rate on octanoic
acid. In-vitro assays show that the mutations we identify increase FadD activity on MCFAs.
These results, homology modeling, and further mutagenesis lead us to hypothesize that our
mutations enhance FadD activity by aiding product exit. This work develops a technique
(inducible degradation of an essential metabolic enzyme) and generates fadD mutants that should
be useful for the production of medium chain biofuels and other compounds.<br>Medical Sciences
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McGilchrist, Peter. "Selection for muscling affects carbohydrate and fatty acid metabolism in beef cattle." Thesis, McGilchrist, Peter (2011) Selection for muscling affects carbohydrate and fatty acid metabolism in beef cattle. PhD thesis, Murdoch University, 2011. https://researchrepository.murdoch.edu.au/id/eprint/14808/.
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Genetic selection to enhance muscularity in beef cattle is desirable to increase retail beef yield and the profitability of the beef industry. However it is unknown how selection for greater muscling will impact on intermediary and muscle energy metabolism which may influence certain attributes of meat quality. In order to assess these impacts of selection for greater muscling in cattle, the physiological mechanisms that underpin the increase in retail beef yield must be identified. This thesis examined the impact of selection for greater muscling on: retail beef yield; muscle glycogen; whole body insulin responsiveness; adrenaline responsiveness of muscle, adipose and liver tissue; and proportion of glycolytic and oxidative myofibres and enzyme activities. This study used 11 high (High), 10 low (Low) and 3 high muscled steers with a myostatin mutation (HighHet) from an Angus herd which had been visually selected for divergence in muscling over 15 years.
The results of the yield test performed at bone-out showed that the HighHet and High muscled steers were the highest yielding with the lowest proportion of fat, while the Low muscling animals were the lowest yielding with the highest proportion of fat. Muscle glycogen and lactate concentration were analysed from four muscle biopsies, taken between 18 and 24 months of age, from the m. semimembranosus (SM), m. semitendinosus (ST) and m. longissimus thoracis et lumborum (LTL) of each animal. The muscle glycogen concentrations which were 6.1% higher in the High steers compared to the Low animals while the HighHet did not differ from either group.
The effect of selection for muscling on whole body insulin responsiveness was measured using the hyperinsulineamic-euglyceamic clamp technique. Insulin was constantly infused at 2 levels, glucose was concurrently infused to maintain euglyceamia, and the steady-state glucose infusion rate (SSGIR) indicated insulin responsiveness. At the low insulin infusion rate of 0.6 mU/kg/min, the SSGIR was 73% higher for the High muscling genotype animals when compared to the Low. At the high insulin infusion rate of 6.0 mU/kg/min, these differences were proportionately less with the High and the HighHet genotypes having only 27% and 34% higher SSGIR than the Low muscled genotype. The High muscled cattle also had 30% higher plasma IGF-1 concentrations compared to the Low muscled cattle. The increased whole body insulin responsiveness in combination with higher IGF-1 concentrations in the High muscled steers is likely to initiate a greater level of protein synthesis, which may partially explain the increased muscle accretion in these animals. Increased insulin responsiveness in the High steers would also increase glycogenesis in the muscle, aligning with the glycogen results.
The effect of selection for muscling on adrenaline responsiveness was measured using 7 adrenaline challenges ranging between 0.2 to 3.0 μg/kg liveweight. Plasma was analysed for NEFA, lactate, glucose and growth hormone concentration and area under curve (AUC) over time was calculated to reflect the tissue responses to adrenaline. The High steers had 30% lower lactate AUC than the Low steers at challenges greater than 2 μg/kg live weight, indicating lower muscle responsiveness at the highest adrenaline doses causing less glycogenolysis. This result also aligns with these animals having more muscle glycogen, thus more muscular animals may reduce the incidence of dark, firm, dry meat that is caused by low levels of glycogen at slaughter. At all levels of adrenaline challenge the High steers had at least 30% greater NEFA AUC, indicating that their adipose tissue was more responsive to adrenaline, resulting in greater lipolysis. In agreement with this response, the High steers had a higher plasma growth hormone concentration, which is likely to have contributed to the increased lipolysis evident in these animals in response to adrenaline. This difference in lipolysis may in part explain the reduced fatness of muscular cattle. There was no effect of selection for muscling on liver responsiveness to adrenaline.
Contrary to our initial hypotheses, the High steers had less glycolytic type IIX myofibres in the LTL and larger average cross-sectional area of myofibres in the SM and ST than their Low muscled counterparts. This suggests that myofibre hypertrophy may be a possible mechanism leading to greater muscle mass of these High muscled animals. This also indicates that breeding for more muscular cattle can actually maintain the oxidative capacity of the muscle, a finding supported by the enzymatic results showing that the High muscled steers had lower activity of lactate dehydrogenase and higher activity of citrate synthase and isocitrate dehydrogenase. The High muscled cattle also had a higher concentration of iron in the LTL, and selection for increased muscling had no impact on pH decline or retail colour stability, factors which both affect meat quality.
The aim of the second experiment was to determine if phenotypic measurements taken at the time of grading for Meat Standards Australia (MSA) could explain variance in ultimate pH (pHu) of carcasses and the probability of a carcass complying with MSA standards for pHu (≤5.7). Analyses of 204,072 carcass records collated by MSA at a Western Australian processor confirmed that more muscular cattle have a higher compliance rate for pHu. An increase in eye muscle area from 40 to 80 cm2, increased pHu compliance by approximately 14%. Therefore animals with greater muscularity had a lower incidence of dark, firm, dry beef supporting the results that High muscled cattle have increased insulin responsiveness, and reduced adrenaline responsiveness, leading to increased glycogen storage at slaughter. Thus, breeding more muscular cattle with eye muscle area greater than 70 cm2 may help alleviate the problem of dark, firm, dry beef. As rib fat depth increased from 0 to 20mm, pHu compliance increased by around 10%. Heavier cattle also had higher compliance than lighter cattle, and younger cattle also had higher compliance rates. This highlights the importance of good nutrition and high muscle glycogen storage prior to slaughter to maximise compliance rates.
The final study examined 81 commercially managed High and Low muscled steers and showed that the effects of muscularity on muscle glycogen were variable as pasture quality and availability changed however there were no negative effects of selection for greater muscling on muscle glycogen, glycogenolysis pre-slaughter, or on the incidence of dark, firm and dry carcasses. Animal temperament assessed using crush score and flight speed measurements did however affect muscle glycogen with the more flighty animals having lower muscle glycogen concentrations.
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CAPUTO, MANUEL. "DEPDC1A, a novel SREBP1 cofactor, regulates fatty acid metabolism in breast cancer." Doctoral thesis, Università degli Studi di Trieste, 2018. http://hdl.handle.net/11368/2924764.
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Breast cancer (BC) figures as the most frequently diagnosed and the leading cause of cancer-related deaths among women worldwide. Despite considerable progress has been made in cancer detection and therapy assignment, several BCs become resistant to therapy and, moreover, a considerable proportion of patients develops metastasis during therapy or experiences relapse.
Growing body of evidence indicates that alterations in tumour metabolism are linked to therapeutic resistance, tumour relapse and dissemination. These altered metabolic traits are caused by genetic alterations and environmental factors.
The most frequently mutated gene in BC is the tumor suppressor TP53, a well-characterized transcription factor, which plays a central role in cellular homeostasis and prevention of tumour growth. In BC missense mutations occur very often in its DNA binding domain, providing neomorphic mutant p53 proteins that lose the wildtype onco-suppressive functions and acquire instead new oncogenic properties (Gain-of-Function). Indeed, mutant p53 proteins establish aberrant interactions with different transcription factors, thus inducing oncogenic transcriptional programs and metabolic reprogramming.
Our previous work outlined a mutant p53 driven signature that promotes aggressiveness in BC in which DEP domain containing 1A (DEPDC1A) emerged as an important mediator of migration and invasiveness (Girardini et al., 2011). DEPDC1A expression is almost undetectable in normal cells, but it is overexpressed in different cancers and its overexpression is associated with poor prognosis. DEPDC1A is a transcriptional cofactor that exists in two different splice variants V1 and V2, but its role in oncogenesis, as well as in a physiological context, remains elusive.
Here we show, through a high-throughput transcriptional analysis, that DEPDC1A is able to impinge on lipid metabolism. In particular we observed that mRNAs belonging to the fatty acids biosynthesis pathway genes ATP-Citrate Lyase (ACLY), Stearoyl-CoA Desaturase 1 (SCD1) and Elongation Of Very Long Chain Fatty Acids 6 (ELOVL6) were consistently downregulated upon DEPDC1A silencing suggesting a key role for this factor in controlling fatty acid metabolism in cancer cells. Indeed, ablation of DEDPC1A caused a significant decrease of lipid droplets content and fatty acid desaturation in MDA-MB-231 cell line.
ACLY, SCD1 and ELOVL6, as a part of fatty acids biosynthesis pathway, are specific targets of Sterol Regulatory Element Binding Protein (SREBP) transcription factors, master regulators of lipid metabolism. Interestingly, protein co-immunoprecipitation and Chromatin Immunoprecipitation assays demonstrated that DEPDC1A physically interacts with SREBP1 and that it is required for an efficient transcriptional activation of this particular subset of genes, thus acting as transcriptional cofactor of SREBP1.
Finally, we showed that DEPDC1A, through SCD1 upregulation, is able to promote aggressive phenotypes, such as migration, and that DEPDC1A overexpression in normal cells is sufficient to induce sensitization toward SCD1 inhibition.
This study unveils a novel oncogenic transcriptional program induced by the aberrant interaction between DEPDC1A and SREBP1 transcription factor that is able to induce fatty acid biosynthesis and desaturation in cancer cells and to establish a metabolic addiction that can be potentially exploited in cancer therapy.
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Brock, Trisha Jane. "Fatty acid metabolism in Caenorhabditis elegans characterization of the delta-9 fatty acid desaturases and identification of a key regulator, nhr-80 /." Online access for everyone, 2005. http://www.dissertations.wsu.edu/Dissertations/Fall2005/t%5Fbrock%5F121505.pdf.
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Montgomery, Colette. "Maternal docosahexaenoic acid (DHA) supplementation and fetal DHA accretion." Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366298.
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MacFarlane, David Peter. "Factors determining the progression of nonalcoholic fatty liver disease : the role of abnormal fatty acid and glucocorticoid metabolism." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5914.
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Obesity and insulin resistance are associated with a constellation of features including hypertension, dyslipidaemia, type 2 diabetes, and premature cardiovascular disease, collectively termed the metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) represents the hepatic component of this syndrome, incorporating a spectrum of liver disease with increasing morbidity and mortality, from simple steatosis, to non-alcoholic steatohepatitis (or NASH), fibrosis, cirrhosis and ultimately hepatocellular carcinoma. However, factors influencing this progression are incompletely understood. In this thesis I sought to investigate pathways which promote hepatic inflammation and fibrosis by studying two contrasting dietary models of NAFLD in mice in which the risk of hepatic inflammation, insulin resistance and fibrosis differ; namely the methionine and choline deficient diet (MCDD) which induces steatohepatitis, hepatic insulin resistance, and weight loss, and the choline deficient diet (CDD) which may be protected from insulin resistance, and leads to steatosis without inflammation or weight loss. I investigated the possible molecular mechanisms underlying these differences, and whether they influenced progression to hepatic fibrosis induced by carbon tetrachloride (CCl4).