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1
Al-Seeni, Madeha N. "Control of hepatic cholesterol esterification". Thesis, University of Nottingham, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293154.
Testo completo
2
Sampson, William James. "The intracellular control of cholesterol metabolism". Thesis, University of Edinburgh, 1988. http://hdl.handle.net/1842/26913.
Testo completoAbstract (sommario):
The liver has a major role in the metabolism of cholesterol, being the main site of lipoprotein assembly and degradation and the only tissue where the metabolism of cholesterol to bile acids occurs. This provides the major pathway for the removal of cholesterol from the body. The results described in this thesis concern the use of specific enzyme inhibitors (58-035, Azacholesterol, Mevinolin) to determine the intracellular use of different sources of cholesterol in monolayers of rat hepatocytes. In particular, the fates of newly synthesized cholesterol from mevalonic acid and cholesterol derived from HDL2 were investigated. Incubation of hepatocyte monolayers with 58-035 resulted in the inhibition of esterification. In the presence of mevalonic acid as a cholesterol source, 58-035 stimulated bile acid synthesis. Azacholesterol inhibited bile acid synthesis, had no effect on cholesterol synthesis, and in the presence of mevalonic acid, stimulated secretion of cholesterol by the hepatocytes; it had no effect on cholesterol esterification. Mevinolin inhibited cholesterol synthesis and as a result inhibited esterification. HDL2, in the presence of mevinolin, was used as a cholesterol source. It stimulated bile acid synthesis and cholesterol esterification. Addition of 58-035 to the system resulted in the inhibition of both esterification and bile acid synthesis. Overall, the results indicated that different intracllular pools of free cholesterol exist and that the inter-relationships of these pools give a complex pattern of flux of intracellular cholesterol between various pathways in the rat hepatocyte.
3
Veen, Jelske Nynke van der. "Nuclear receptors in control of cholesterol transport". [S.l. : Groningen : s.n. ; University Library Groningen] [Host], 2007. http://irs.ub.rug.nl/ppn/304675490.
Testo completo
4
Dunn, Stuart Antony. "Hormone-sensitive lipase and the control of lipid metabolism in the human macrophage foam cell". Thesis, University of Newcastle Upon Tyne, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311114.
Testo completo
5
Sims, Helen M. "Transcriptional control of microsomal triglyceride transfer protein gene expression in the hamster". Thesis, University of Nottingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366470.
Testo completo
6
Martinic, Goran (Gary), of Western Sydney Hawkesbury University, of Science Technology and Environment College e School of Environment and Agriculture. "Cyclodextrins as potential human anti-atherosclerotic agents". THESIS_CSTE_EAG_Martinic_G.xml, 2001. http://handle.uws.edu.au:8081/1959.7/129.
Testo completoAbstract (sommario):
Cyclodextrins (CDs) are naturally occurring cyclic oligosaccharides. Since it is believed that OxC blocks the removal of normal cholesterol from cells in the artery wall, it is possible that selective removal of OxC in the vessel wall in-vivo may prevent or reverse atherosclerosis.As a prelude to major studies, this research project was designed to answer two critical questions; 1/. What is the best route for delivery of CD. 2/. How do animals (apoE-/- mice) tolerate it. Pilot studies were established and results noted. These studies have provided valuable information in the apoE-/- mouse for subsequent studies to prevent or reverse atherosclerosis in this animal model.Master of Science (Hons)
7
Witsken, Colleen. "The Effect of Parental Control Over Child-Feeding on Compliance to Dietary Recommendations to Lower Blood Cholesterol". University of Cincinnati / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1179758468.
Testo completo
8
Dun, Alison. "Spatial and temporal control of regulated exocytosis by protein and lipid interactions". Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/8087.
Testo completoAbstract (sommario):
Cellular communication requires the transport of chemical messengers between intracellular compartments and from cell to cell. The regulated exocytosis of a secretory vesicle at the plasma membrane involves the merger of two bilayers, with markedly different lipid composition, within a millisecond time scale. The spatial and temporal control of the protein and lipid complement at these fusion sites is essential. A highly conserved family of proteins are known to drive this fusion event; SNAP-25 and syntaxin-1 (t-SNAREs) associate at the plasma membrane in a 1:1 stoichiometry to provide a binding site for the vesicle-membrane protein synaptobrevin (v-SNARE). The formation of this complex and subsequent fusion requires accessory proteins for efficient calcium-triggered exocytosis; which of these proteins facilitate the initial attachment of vesicle to the plasma membrane prior to fusion is still under debate. Specific sites for vesicle fusion have been proposed and the organisation of lipids and proteins at these fusion sites has been extensively investigated with limited spatial and temporal resolution; however the presence of raft-forming lipids at these sites as well as the arrangement of SNARE proteins at the molecular level is still under contention. The data presented within this thesis aims to elucidate the protein and lipid environment at the fusion site using super-resolution microscopy and advanced vesicle tracking. Under diffraction-limited microscopy the t-SNAREs are visualised as 200 nm homogenous clusters; however I have used single molecule localisation microscopy to reveal a more complex heterogeneous molecular arrangement. Quantification of lipid order exclusively at the plasma membrane provided insight into the influence of cholesterol-induced lipid arrangement on SNAP-25 localisation. In addition the t-SNARE interaction was investigated using TCSPC-FLIM identifying two lipid-order-dependent conformations in distinct clusters at the plasma membrane. Extensive vesicle tracking at optimum sampling rates demonstrated the ‘sampling’ behaviour of LDCVs and allowed characterisation of vesicle fusion sites. In summary I find that vesicles exhibit preference for residence and probably fusion at regions of plasma membrane with a low t-SNARE density; these proteins appear to exert control over exocytosis by adopting alternative conformations that are under cholesterol-induced regulation.
9
Kangas-Kontio, T. (Tiia). "Genetic background of HDL-cholesterol and atherosclerosis:linkage and case-control studies in the Northern Finnish population". Doctoral thesis, Oulun yliopisto, 2011. http://urn.fi/urn:isbn:9789514295812.
Testo completoAbstract (sommario):
Abstract Coronary heart disease (CHD), a manifestation of atherosclerosis, is the leading single cause of death in Finland. CHD is affected by numerous genetic and environmental factors, their combined effects and interactions between them. Low HDL-cholesterol (HDL-C) is an independent risk factor for atherosclerosis and the most common dyslipidemia associated with early onset CHD, but the mechanisms regulating HDL-C levels and protecting from atherosclerosis are still not completely understood. Adiponectin is a hormone that is secreted by adipose tissue and has several anti-atherosclerotic effects. There is multiple evidence suggesting that adiponectin could protect against CHD via positive effects on HDL metabolism. Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor that has a potentially conflicting role in atherosclerosis; it may have protecting or predisposing effects. The objective of this thesis was to study the genetic background of HDL-C regulation and atherosclerosis. Three studies were executed using extended families with CHD or case-control setting, with samples collected from Northern Finland. In the first study, seven chromosomal regions showing suggestive evidence of linkage were identified for HDL-C regulation, using genome-wide linkage approach. In the second study, we found a strong correlation between HDL-C and adiponectin, but failed to show evidence of a shared genetic background. However, a genetic correlation between adiponectin and low-density lipoprotein-cholesterol was revealed. We also studied the genetic regulation of adiponectin, and for the first time its most active form, high-molecular weight adiponectin, and found suggestive evidence of linkage to three chromosomal regions. In the third study, it was discovered that the studied VEGF gene polymorphisms did not have a major effect on atherosclerosis quantified as carotid intima-media thickness or the risk of acute myocardial infarction (AMI). This thesis presents potential regions for the genetic regulation of HDL-C and adiponectin and gives new information about their relationship and the effect of VEGF polymorphisms in atherosclerosis. The strong correlation between adiponectin and HDL-C was further strengthened, but we failed to show a shared genetic background between themTiivistelmä Sepelvaltimotauti, eräs valtimonkovettumataudin ilmentymä, on yleisin yksittäinen kuolinsyy maassamme. Taudin syntyyn vaikuttavat lukuisat geneettiset ja ympäristötekijät sekä niiden väliset yhteis- ja vuorovaikutukset. Pieni HDL-kolesterolipitoisuus on valtimonkovettumataudin itsenäinen riskitekijä ja yleisin kolesterolipoikkeavuus, joka liittyy varhain ilmenevään sepelvaltimotautiin. HDL-kolesterolin vaihtelun syitä ja tämän "hyvän kolesterolin" sepelvaltimotaudilta suojaavia vaikutusmekanismeja ei kuitenkaan pystytä täysin selittämään. Adiponektiini on rasvakudoksen tuottama hormoni, jonka sepelvaltimotaudilta suojaavan ominaisuuden on ehdotettu johtuvan siitä, että se vaikuttaisi HDL-kolesterolin aineenvaihduntaan. VEGF (vascular endothelial growth factor) on verisuonten sisäseinämissä vaikuttava kasvutekijä, jolla saattaa olla joko sepelvaltimotaudilta suojaavia tai sille altistavia vaikutuksia. Väitöskirjatyön tavoitteena oli tutkia HDL-kolesterolin ja valtimonkovettumataudin geneettistä taustaa. Kolmessa osatyössä tutkittiin suuria pohjoissuomalaisia sepelvaltimotautisukuja; lisäksi käytettiin väestö- ja potilasaineistoja. Ensimmäisessä tutkimuksessa löydettiin koko genomin kytkentäkartoitusmenetelmällä seitsemän kromosomialuetta, jotka saattavat vaikuttaa HDL-kolesterolin säätelyyn. Toisessa tutkimuksessa selvitettiin adiponektiinin, ja ensimmäistä kertaa myös sen aktiivisimman muodon, HMW-adiponektiinin geneettistä taustaa. Kytkentäanalyysissä saatiin viitteitä kolmesta adiponektiineja mahdollisesti säätelevästä kromosomialueesta. Havaittiin myös, että HDL-kolesterolin ja adiponektiinin pitoisuudet korreloivat vahvasti keskenään, mutta yhteistä geneettistä säätelytekijää ei pystytty osoittamaan. LDL-kolesterolin ja adiponektiinin välillä kuitenkin havaittiin geneettinen korrelaatio. Kolmannessa tutkimuksessa todettiin, ettei tutkituilla VEGF-geenin nukleotidimuutoksilla todennäköisesti ole merkittävää syy-yhteyttä valtimonkovettumatautiin kaulavaltimoiden sisäseinämän paksuudella tai sydäninfarktiriskillä mitattuna. Tämä tutkimus tuo uutta tietoa HDL-kolesterolin ja adiponektiinin geneettisestä säätelystä ja niiden suhteesta sekä VEGF-geenin nukleotidimuutosten osuudesta valtimonkovettumataudissa. Tutkimus vahvistaa edelleen HDL-kolesterolin ja adiponektiinin yhteyden, muttei pysty osoittamaan niille yhteistä geneettistä tekijää
10
Kranz, Eylath. "Dietary habits and life style in the etiology of cholesterol gallstone disease a matched case control study /". [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=968492649.
Testo completo
11
Esche, Curtis A. "The effects of streptozotocin-induced diabetes on control of serum cholesterol levels in female strain A/ST mice". Virtual Press, 1991. http://liblink.bsu.edu/uhtbin/catkey/834628.
Testo completoAbstract (sommario):
Diabetics often have elevated levels of serum lipids and cholesterol and increased risk of cardiovascular disease. Streptozotocin-induced diabetes was used to determine whether elevated serum cholesterol levels in diabetics are due to loss of control of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, which catalyzes the committed step in cholesterol synthesis. Strain A/ST female mice were fed 10% corn oil diets, half with 2% cholesterol. Experimental groups were injected with 9.0 mg streptozotocin / 100g body weight. Diabetes was confirmed by weight loss, elevated blood sugars, and enlarged spleens. Reductase activity was assayed spectrophotometrically. Serum cholesterol levels were determined by gas liquid chromatography. Both diabetic and control mice fed cholesterol had elevated serum cholesterol levels and decreased reductase activities. These observations suggest that HMG CoA reductase is not the primary control point in the control of serum cholesterol levels in diabetic mice. The increase in serum cholesterol in the SI mice was not more than in the control group, suggesting that increased serum cholesterol is not a key factor in the control of coronary heart disease and related diseases in diabetics. The HMG CoA reductase activity was reduced in both SI and control mice fed 2% cholesterol, but not significantly, possibly due to a small sample size. Other substances that control serum cholesterol are all density classes of lipoproteins (high, intermediate, low, and very low) as well as the chylomicrons.Department of Biology
12
Huwait, Etimad A. "Liver-X-receptor-mediated expression of key genes in macrophages implicated in the control of cholesterol homeostasis and atherosclerosis". Thesis, Cardiff University, 2008. http://orca.cf.ac.uk/54714/.
Testo completoAbstract (sommario):
Atherosclerosis is a leading cause of morbidity and mortality in the western world. The deposition of lipoprotein cholesterol in the arterial wall is a critical early step in the pathogenesis of atherosclerosis. These atherogenic lipoproteins are then taken up by macrophages to transform into lipid-loaded foam cells. ATP-binding cassette transporter-Ai (ABCAi) is a membrane-bound protein that mediates efflux of cholesterol from cells, such as macrophages. Tangier disease, which arises due to mutations in the ABCAi gene, is associated with foam cells in a number of tissues and premature atherosclerosis. Proteins in HDL, such as apolipoprotein E (apoE), act as acceptors of cholesterol released from macrophages via the action of ABCAi, and take it to the liver where it can be excreted through the bile system. Increasing the expression of both ABCAi and apoE is therefore considered as a potential therapeutic approach for the prevention or treatment of atherosclerosis. Liver-X-receptors (LXRs) are members of a subfamily of nuclear receptors that are potent activators of ABCAi and apoE expression. Agonists of LXRs inhibit macrophage foam cell formation in vitro and atherosclerosis in mouse models of the disease. The signalling pathways through which LXR agonists induce the expression of ABCAi and apoE expression in macrophages are not known. The major aim of the studies presented in this thesis was to investigate such signalling pathways using the human macrophage THP-1 cell line as a model system with key findings confirmed in primary cultures. Both natural LXR agonists, such as combinations of 22-(R)-hydroxycholesterol (22-(R)-HC) and 9-cis-retinoic acid (9CRA), and synthetic ligands induced the expression of ABCAi and apoE. Such an induction of ABCAi and apoE expression was attenuated by treatment of the cells with pharmacological inhibitors of c-Jun-N-terminal kinase/stress- activated kinase (JNK/SAPK) and phosphoinositide-3-kinase (PI3K) pathways. The action of 22-(R)-HC and 9CRA was associated with activation of JNK/SAPK, its upstream component SEK1/MKK4 and its down-stream target c-Jun along with the key target for PI3K, protein kinase B (PKB). The role of these pathways was confirmed further by analysing the action of expression of dominant negative forms of key proteins on the activation of ABCAi promoter. In addition, small interfering RNA-mediated knockdown of JNK/SAPK was found to attenuate the induction of apoE expression. The action of these pathways culminated at the level of activator protein-1, a transcription factor that contains c-Jun, and whose binding sites are present in the regulatory regions of both the apoE and ABCAi genes. Finally, a potential cross-talk between the JNK/SAPK and PI3K pathways was identified in which protein kinase C played an important role. In conclusion, the studies presented in this thesis demonstrated, for the first time, an important role for a pathway involving PKB, PKC and JNK/SAPK cascade in the activation of ABCAi and apoE expression by LXR agonists, which has implications to macrophage foam cell formation and atherosclerosis.
13
Akenhead, Michael L. "The Influence of Cholesterol-Related Membrane Fluidity on the Shear Stress Control of Neutrophil Adhesion and Its Implications in Hypercholesterolemia". UKnowledge, 2016. http://uknowledge.uky.edu/cbme_etds/41.
Testo completoAbstract (sommario):
Hypercholesterolemia is a significant risk factor in the development of cardiovascular disease and is associated with chronic leukocyte adhesion in the microvasculature. While the underlying mechanisms behind this have yet to be determined, it may be possible that hypercholesterolemia impairs the fluid shear stress (FSS) inactivation of neutrophils through the rigidifying effect of cholesterol on membrane fluidity. FSS restricts surface expression of CD18 integrins through cathepsin B (ctsB) proteolysis, which minimizes neutrophil adhesivity. If hypercholesterolemia blocks FSS mechanotransduction, then the inhibition of CD18 cleavage may link pathologic blood cholesterol elevations with dysregulated neutrophil adhesion. We hypothesized that elevated cholesterol contributes to dysregulated neutrophil adhesion by impairing ctsB FSS-induced CD18 cleavage through membrane fluidity changes.
In the first part of this study, we demonstrated that FSS-induced CD18 cleavage is a robust response of neutrophils and involves selective cleavage of macrophage 1-antigen (Mac1) through ctsB proteolysis. The second part of this study confirmed that ctsB regulates neutrophil adhesion through its proteolytic actions on Mac1, an important integrin involved in adhesion and chemotaxis. Specifically, ctsB accelerated neutrophil motility through an effect on Mac1 integrins during pseudopod retraction. Furthermore, by using a flow-based assay to quantify the mechanoregulation of neutrophil adhesivity, we demonstrated that FSS-induced ctsB release promoted neutrophil detachment from platelet-coated substrates and unstimulated endothelium. For the third part of this study, we linked cholesterol-related membrane fluidity changes with the ability of FSS to restrict neutrophil adhesion through Mac1. We also determined that pathologic cholesterol elevations associated with hypercholesterolemia could block FSS-induced Mac1 cleavage and were linked to disrupted tissue blood flow. This was accomplished using low-density lipoprotein receptor deficient (LDLR-/-) mice fed a high-fat diet.
Ultimately, the results provided in the present study confirmed that cholesterol-related changes in membrane fluidity blocked the ability of ctsB to regulate neutrophil adhesion through FSS-induced Mac1 cleavage. This implicates an impaired neutrophil FSS mechanotransduction response in the dysregulation of neutrophil adhesion associated with hypercholesterolemia. Since dysregulated adhesion may be one of the earliest upstream features of cardiovascular disease associated with hypercholesterolemia, the present study provides a foundation for identifying a new mechanobiological factor in the pathobiology of microcirculatory dysfunction.
14
Timby, Niklas. "Effects of feeding term infants low energy low protein formula supplemented with bovine milk fat globule membranes". Doctoral thesis, Umeå universitet, Pediatrik, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-88192.
Testo completoAbstract (sommario):
Background Observational studies have shown that early nutrition influences short- and long-term health of infants. Formula-fed infants have higher protein and energy intakes and lower intakes of several biologically active components present in human milk. Some of these are present in the milk fat globule membrane (MFGM). The aim of the present study was to examine the effects of feeding term infants an experimental low energy low protein formula supplemented with bovine milk fat globule membranes. Our hypothesis was that infants fed experimental formula (EF), compared to infants fed standard formula (SF), would have outcomes more similar to a breast-fed reference (BFR) group. Methods In a double-blinded randomized controlled trial, 160 exclusively formula-fed, healthy, term infants were randomized to receive EF or SF from <2 to 6 months of age. A BFR group consisted of 80 breast-fed infants. Measurements were made at baseline, 4, 6 and 12 months of age. The EF had lower energy (60 vs. 66 kcal/100 mL) and protein (1.20 vs. 1.27 g/100 mL) concentrations, and was supplemented with a bovine MFGM concentrate. Results At 12 months of age, the EF group performed better than the SF group in the cognitive domain of Bayley Scales of Infant Development, 3rd Ed. During the intervention, the EF group had a lower incidence of acute otitis media than the SF group, less use of antipyretics and the EF and SF groups differed in concentrations of s-IgG against pneumococci. The formula-fed infants regulated their intakes by increasing meal volumes. Thus, there were no differences between the EF and SF groups in energy or protein intakes, blood urea nitrogen, insulin or growth including body fat percent until 12 months of age. Pressure-to-eat score at 12 months of age was reported lower by parents of formula-fed infants than by parents of breast-fed infants, indicating a low level of parental control of feeding in the formula-fed groups. Neither high pressure-to-eat score nor high restrictive score was associated with formula feeding. During the intervention, the EF group gradually reached higher serum cholesterol concentrations than the SF group, and closer to the BFR group. At 4 months of age, there was no significant difference in the prevalence of lactobacilli in saliva between the EF and SF groups. Conclusions Supplementation of infant formula with a bovine MFGM fraction enhanced both cognitive and immunological development in formula-fed infants. Further, the intervention narrowed the gap in serum cholesterol concentrations between formula-fed and breast-fed infants. The lower energy and protein concentrations of the EF were totally compensated for by a high level of self-regulation of intake which might, at least partly, be explained by a low level of parental control of feeding in the study population. The findings are of importance for further development of infant formulas and may contribute to improved short- and long-term health outcomes for formula-fed infants.
15
Martinic, Gary. "Cyclodextrins as potential human anti-atherosclerotic agents". Thesis, View thesis View thesis, 2001. http://handle.uws.edu.au:8081/1959.7/129.
Testo completoAbstract (sommario):
Cyclodextrins (CDs) are naturally occurring cyclic oligosaccharides. Since it is believed that OxC blocks the removal of normal cholesterol from cells in the artery wall, it is possible that selective removal of OxC in the vessel wall in-vivo may prevent or reverse atherosclerosis.As a prelude to major studies, this research project was designed to answer two critical questions; 1/. What is the best route for delivery of CD. 2/. How do animals (apoE-/- mice) tolerate it. Pilot studies were established and results noted. These studies have provided valuable information in the apoE-/- mouse for subsequent studies to prevent or reverse atherosclerosis in this animal model.
16
Brand, Céline. "Une nouvelle cible de TGF(bêta)1 dans le contrôle de la stéroidogenèse corticosurrénalienne : StAR (protéine régulatrice du transport intramitochondrial du cholestérol)". Université Joseph Fourier (Grenoble ; 1971-2015), 1998. http://www.theses.fr/1998GRE10137.
Testo completoAbstract (sommario):
La famille des facteurs de croissance transformant (tgf) est constituee d'une trentaine de peptides dimeriques qui controlent la croissance et la differenciation de nombreux types cellulaires. Tgf1 est un regulateur autocrine de la steroidogenese qui inhibe l'expression de la steroide 17-hydroxylase (p-450c17). Au cours de ce travail, j'ai identifie une nouvelle cible de tgf1 dans la voie de biosynthese des hormones corticosteroides : star (steroidogenic acute regulatory protein), une proteine mitochondriale indispensable au transfert du cholesterol de la membrane externe a la membrane interne de la mitochondrie. Dans les cellules fasciculo-reticulees bovines, tgf1 diminue le niveau d'expression de l'arnm de star de facon dependante du temps et de la concentration. Cette regulation requiert une neosynthese proteique. L'etude comparative de la regulation par tgf1 de l'expression de star et de p-450c17 apres differents jours de culture in vitro des cellules fasciculo-reticulees bovines indique que, dans les conditions les plus proches de la physiologie, star est la cible majeure de tgf1. Le mecanisme moleculaire de regulation de l'expression de star par tgf1 a ete etudie par diverses approches experimentales. Le facteur de transcription sf-1 (steroidogenic factor-1) ne semble pas implique dans cette regulation. Par contre, smad3, une proteine cytoplasmique phosphorylee par les recepteurs de tgf1, reproduit l'inhibition de l'expression de star dans la lignee cellulaire humaine nci-h295r et semble etre indispensable a cet effet de tgf1. Il est possible que ces observations originales puissent etre generalisees a d'autres types cellulaires endocriniens (testicules, ovaire) ou une action de tgf1 sur le transport du cholesterol a ete suggeree.
17
Zheng, Hui. "Apolipoprotein A-I lipidation in primary mouse hepatocytes: Separate controls for phospholipid and cholesterol transfers". Thesis, University of Ottawa (Canada), 2005. http://hdl.handle.net/10393/27101.
Testo completoAbstract (sommario):
The liver is the site for both apolipoprotein A-I (apoA-I) synthesis and ATP-binding cassette transporter A1 (ABCA1) expression. To investigate the function of hepatic lipidation of apoA-I by cholesterol and phospholipid, and delineate the role of hepatic ABCA1 in these lipidation pathways, I have expressed human apoA-I by adenovector-mediated gene transfer into primary mouse hepatocytes. Kinetic studies demonstrate that newly synthesized apoA-I acquires both cholesterol and phospholipid during secretion and at the cell surface. Approximately 80% of the phospholipidation, and only 40--60% of the cholesterol lipidation of apoA-I is ABCA1-dependent. Hepatic apoA-I cholesterol lipidation depends on the active transfer from intracellular compartments to the cell surface. Under ABCA1 deficiency, both apoA-I and cholesterol associated with apoA-I in high-density lipoprotein (HDL) fraction decrease, but the nature of the lipoprotein particles is not affected. Furthermore, this study demonstrates the different regulation and/or controls are required for apoA-I cholesterol lipidation and phospholipidation.
18
Battle, Robert A. "Comparison of total and high-density lipoprotein cholesterol in male recreational swimmers and sedentary controls". Thesis, Virginia Polytechnic Institute and State University, 1985. http://hdl.handle.net/10919/104291.
Testo completo
19
Nishiga, Masataka. "MicroRNA-33 Controls Adaptive Fibrotic Response in the Remodeling Heart by Preserving Lipid Raft Cholesterol". 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225501.
Testo completo
20
Roullet, Jean-Baptiste. "Role des derives non steroliques de l'acide mevalonique dans le controle du tonus vasculaire (doctorat : structure et fonctionnement des systemes biologiques integres)". Paris 11, 1998. http://www.theses.fr/1998PA114822.
Testo completo
21
Journoud, Mélanie. "The effect of plant sterols on lipid profiles and cholesterol kinetics of hypercholesterolemic individuals with type 2 diabetes compared with non-diabetic controls /". Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=80296.
Testo completoAbstract (sommario):
The objective of this study was to compare the effect of phytosterols (PS) on lipid profiles and cholesterol kinetics of hypercholesterolemic individuals with or without type 2 diabetes. It was hypothesised that the response to PS would differ between both groups due to different lipid metabolism. During this randomised, double blind, crossover trial, participants consumed a controlled diet with placebo or PS for 21 days.Plasma total cholesterol (TC) decreased with placebo and PS (10.9% and 9.7% in non-diabetic versus 11.6% and 13.6% in diabetic participants, p < 0.05). Plasma low-density lipoprotein cholesterol (LDL) significantly decreased with PS in both groups. The reduction in LDL with PS was greater in diabetic compared to non-diabetic individuals (29.8% versus 14.9%, p < 0.05). Cholesterol absorption decreased on average (p = 0.06) by 26.5% with PS compared with placebo in the diabetic group only. Therefore, a controlled heart healthy diet reduced TC and LDL concentrations in non-diabetic and diabetic individuals. Adding PS as adjuncts to a hypocholesterolemic dietary treatment was associated with lower LDL concentrations and cholesterol absorption in hypercholesterolemic participants with type 2 diabetes.
22
Pereira, Patricia Helena Gilberto Rios. "Lipoproteína de alta densidade (HDL) isolada de portadores de diabete melito tipo 2 com controle glicêmico inadequado favorece o acúmulo de colesterol em macrófagos". Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-08032010-102308/.
Testo completoAbstract (sommario):
No diabete melito tipo (DM) 2, a glicoxidação da LDL favorece o acúmulo de colesterol nos macrófagos da parede arterial, enquanto que as modificações da HDL alteram o transporte reverso do colesterol e reduzem sua capacidade ateroprotetora. O objetivo deste estudo foi avaliar a concentração de colesterol livre (CL) e esterificado (CE) em macrófagos, resultante da incubação conjunta de LDL e HDL isoladas de indivíduos portadores de DM 2 (D) com controle glicêmico inadequado, ou de indivíduos controles não diabéticos (C). LDL e HDL isoladas do plasma por ultracentrifugação por gradiente descontínuo de densidade foram incubadas simultaneamente (100g proteína/mL de meio) em macrófagos de peritônio de camundongos, durante 48 h, a 37°C, de acordo com os seguintes esquemas: LDL(C); LDL(C)+HDL(C); LDL(C)+HDL(C) pool; LDL(D); LDL(D)+HDL(D) ou LDL(D)+ HDL(C) pool. O conteúdo celular de CL e CE (linoleato, oleato e palmitato) foi analisado por HPLC (g/mg de proteína celular). A idade, IMC e triglicérides plasmáticos, assim como a glicemia de jejum e HbA1c, eram maiores no grupo DM, em comparação com o grupo C. Nas incubações com LDL(D) + HDL(D), observou-se maior conteúdo celular de colesterol total (607 ± 99; p = 0,033) e esterificado (430 ± 86; p = 0,023) em comparação com LDL(D) (356 ± 73; 209 ± 51, respectivamente), e somente do colesterol esterificado comparado com LDL(D) + HDL(C) pool (208 ± 70; p = 0,023). Os macrófagos com LDL(D) + HDL(D) apresentaram maior conteúdo de colesterol total (607 ± 99; p = 0,01), CL (177 ± 21; p = 0,03) e CE (430 ± 86; p = 0,02) em comparação com LDL(C) + HDL(C) pool (266 ± 66, 89 ± 16 e 176 ± 53, respectivamente). O acúmulo de colesterol esterificado nos macrófagos foi decorrente da maior formação de colesterol linoleato e oleato. A análise da composição das HDL(D) mostrou menor conteúdo de apo A-I em relação aos lípides, comparada com HDL(C). Em conclusão, a incubação simultânea de LDL(D) + HDL(D) provocou maior acúmulo de colesterol em macrófagos, em comparação à incubação de LDL(D) isoladamente ou de LDL(C) + HDL(C) pool. Estes resultados sugerem que a HDL de portadores de DM 2 mal compensados favorece o maior acúmulo de colesterol em macrófagos.The development of atherosclerosis in type 2 diabetes mellitus (DM2) is associated with lipoprotein (LP) modifications. Glycoxidized LDL increases macrophage cholesterol accumulation whereas HDL modifications impair the reverse cholesterol transport and atheroprotective properties. The objective of this study was to evaluate the cholesterol content of mouse peritoneal macrophage (MPM) after their simultaneous incubation with LDL+HDL or LDL alone from poorly controlled DM2 (D, n=11), and from non-diabetic control individuals (C, n=11). LP were isolated by discontinuous density gradient ultracentrifugation and incubated (100g protein/mL) with MPM (48h), according to the following protocol: LDL(C); LDL(C)+HDL(C); LDL(C)+HDL(C) pool; LDL(D); LDL(D)+HDL(D) or LDL(D)+ HDL(C) pool. The cellular contents of free (FC) and of esterified cholesterol (EC: linoleate, oleate and palmitate) were measured by HPLC (g/mg of cell protein). Age, BMI, fasting plasma glucose, HbA1c and triglycerides were higher in D as compared to C. The incubation with LDL(D)+HDL(D) increased MCM TC (mean ± SEM) (607 ± 99; p = 0,033) and EC (430 ± 86; p = 0,023) contents compared to LDL(D) alone (356 ± 73; 209 ± 51, respectively). Also, MPM EC content was higher compared to LDL(D)+HDL(C)pool (208 ± 70; p = 0,023). MPM incubated with LDL(D)+HDL(D) presented greater contents of TC (607 ± 99; p = 0,01), FC (177 ± 21; p = 0,03) and of EC (430 ± 86; p = 0,02) compared to the LDL(C)+HDL(C)pool (266 ± 66, 89 ± 16 e 176 ± 53, respectively). The cellular EC content was ascribed to accumulations of linoleate and oleate. Analysis of the HDL composition showed higher lipid/apo A-I ratio in HDL(D) compared to HDL(C). In conclusion, the simultaneous incubation of LDL(D)+HDL(D) induces greater cholesterol accumulation in macrophage compared to LDL(D) and LDL(C)+HDL(C)pool. These results suggest that uncontrolled DM2 HDL favours the cellular cholesterol accumulation.
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Padoveze, Amanda Felippe. "Cinética plasmática e biodistribuição de colesterol livre e colesterol esterificado de uma nanoemulsão (LDE) que se liga aos receptores de LDL em animais controle e com indução de aterosclerose". Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/5/5131/tde-25062009-120520/.
Testo completoAbstract (sommario):
Estudos anteriores em nosso laboratório demonstraram que pacientes portadores de DAC apresentam diferenças no metabolismo do CL e CE de uma nanoemulsão artificial rica em colesterol (LDE), nos quais o CL apresentou maior remoção plasmática e depósito arterial. Dando continuidade a esta linha de pesquisa, neste trabalho foram avaliadas a cinética plasmática, representada pela taxa fracional de remoção (TFR), e a captação do 3H-colesterol livre (3H - CL) e 14C - colesterol esterificado (14C - CE) da LDE por segmentos arteriais e por órgãos de coelhos normais (n=17) e coelhos submetidos à indução de aterosclerose por dieta rica em colesterol (1%) (n=13). Além disso, avaliou-se a captação in vitro do 3H CL e do 14C CE da LDE por células endoteliais aórticas de coelhos. Por último, foi avaliada a influência da inibição da enzima lecitina-colesterol aciltransferase (LCAT), e indiretamente, a esterificação do CL em ratos normais (n=9) e tratados com diazepam (n=9). Em coelhos que receberam dieta normal, não houve diferença entre a remoção plasmática do 3H - CL e do 14C - CE. Em coelhos que desenvolveram hiperlipidemia e aterosclerose através de dieta rica em colesterol, o 3H - CL foi removido mais rapidamente da circulação do que o 14C - CE (p<0,05), entretanto houve maior captação de 14C - CE do que de 3H - CL no arco aórtico (p<0,05). Em ambos os grupos, os principais órgãos captadores de colesterol da LDE foram fígado, pulmão, adrenais e baço (p<0,05). Tanto a TRF quanto a captação hepática de 3H - CL e 14C - CE foram menores no grupo que recebeu a dieta rica em colesterol. Em células endoteliais aórticas de coelhos, a captação de 3H - CL foi maior que a de 14C CE independente da massa de LDE incubada (p<0,01). Em ratos, não houve diferença entre a captação das duas formas de colesterol da LDE pela aorta no grupo controle, entretanto, quando a atividade da LCAT foi diminuída pelo tratamento com diazepam, a captação arterial de 3H - CL foi maior do que a de 14C - CE (p< 0,01). A hiperlipidemia e distúrbios no processo de estabilização do colesterol, favorecem a dissociação entre o CL e o CE das lipoproteínas, e podem elevar o risco de desenvolvimento da aterosclerose, assim como agravar o processo de aterogênese.I n previously studies, it was shown that free cholesterol (FC) and cholesterol ester (CE) of a cholesterol-rich nanoemulsion (LDE) behaves differently in patients with coronary artery disease (CAD). The FC plasma clearance and arterial deposition is greater than CE. In the present study we evaluate the plasma kinetics, estimated by the fractional clearance rate (FCR), and the tissue uptake of 3H-free cholesterol (3H FC) and of 14C cholesterol ester (14C - CE) of LDE by arterial segments and organs of rabbits with (n=13) and without atherosclerosis (n=17). Furthermore, it was evaluated the in vitro uptake of 3H FC and 14C - CE by rabbit aortic endothelial cells. Finally, it was evaluated the inhibition of the enzyme lecithin-cholesterol acyltransferase (LCAT), and indirectly, the FC esterification in rats non-treated (n=9) and treated with diazepam (n=9). In rabbits without atherosclerosis that received an standard diet there was no difference between the plasma clearance of 3H FC and 14C CE. In rabbits with hyperlipidemia and atherosclerosis induced by the cholesterol-rich diet the 3H - FC was removed faster than 14C - CE (p<0.05), however the arch aortic uptake of 14C CE was greater than of 3H - FC (0p<0.05). In both groups, liver, lungs, adrenals and spleen were the principal sites of LDE cholesterol uptake. The FCR and tissue uptake were smaller in rabbits with than those without atherosclerosis. In rabbit aortic endothelial cells the 3H - FC uptake was greater than 14C CE independently of incubated LDE mass (p<0.01). In control rats there was no difference on the arterial uptake of both cholesterol forms of LDE, but when the LCAT activity was diminished by the diazepam treatment, the arterial uptake of 3H FC were greater than 14C CE (p< 0.01). The hyperlipidemia and cholesterol stability alterations may lead to dissociation between lipoproteins FC and CE. This dissociation may increase the risk for atherosclerosis and likewise enhance the severity of atherosclerosis.
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Neto, Oscar Giese Laverdy. "Efeitos do controle glicêmico sobre os lípides séricos e na transferência lipídica para a HDL em pacientes com diabetes mellitus tipo 2: novos achados no status do colesterol não esterificado". Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-14012015-154739/.
Testo completoAbstract (sommario):
Introdução:Uma das causas da doença cardiovascular do diabético é a dislipidemia associada ao diabetes mellitus tipo 2 (DM2), caracterizada basicamente por hipertrigliceridemia e baixa concentração de HDL-colesterol. O bom controle da glicemia geralmente resulta em diminuição dos triglicerídeos plasmáticos, mas há controvérsia na literatura quanto aos níveis de HDL-colesterol e outros parâmetros lipídicos. As transferências lipídicas para a HDL têm importante função na sua formação e remodelamento e no seu papel antiaterogênico do transporte reverso do colesterol. A transferência de lípides entre as lipoproteínas é bidirecional e depende da estrutura e concentração da lipoproteína doadora e receptora, assim como da ação das proteínas de transferências, CETP e PLTP. Objetivo:Investigar as relações dos níveis glicêmicos com as transferências lipídicas para a HDL e com outros parâmetros do metabolismo lipídico em pacientes com DM2. Métodos:143 pacientes com DM2, que não estavam usando drogas hipolipemiantes, foram selecionados e separados em dois grupos: grupo com hemoglobina glicada (HbA1c) <= 6,5% (n=62) e grupo com HbA1c > 6,5% (n=81). O método in vitro de transferência lipídica para a HDL foi realizado através da incubação sob agitação, por 1 hora, de uma nanoemulsão doadora contendo colesterol esterificado e não esterificado, fosfolipídios e triglicerídeos, marcados radioativamente, com o plasma do paciente, seguido de precipitação química e contagem dos lipídios radiomarcados transferidos para HDL. Outras determinações plasmáticas do metabolismo lipídico também foram realizadas. Foi também verificado o percentual de pacientes nos dois grupos com o perfil lipídico dentro das metas estabelecidas pela American Diabetes Association. Pacientes com ou sem uso de insulina e com níveis maiores e menores de ácidos graxos livres (AGL) foram comparados quanto aos parâmetros estudados. Resultados:O grupo HbA1c > 6,5% apresentou maior trigliceridemia (205±115 vs 140±54mg/dl; p < 0,0001) e colesterol não esterificado (36,4±7,6 vs 33,7±5,7mg/dl; p > 0,05), além de apresentar maior concentração de triglicerídeos na partícula de HDL (9,2±2,8 vs 8,1±2,3%; p < 0,05), do que o grupo HbA1c<=6,5%. As concentrações de triglicerídeos, colesterol total e não esterificado e também o colesterol da fração não-HDL correlacionaram-se positivamente com a HbA1c (r=0,25, r=0,19, r=0,18, r=0,17, respectivamente, p < 0,05). A concentração de colesterol esterificado da HDL correlacionou-se negativamente com a HbA1c (r=-0,19, p < 0,05). Os pacientes com HbA1c <= 6,5% atingiram mais a meta trigliceridêmica do que os com HbA1c > 6,5% (66 vs 37%; p < 0,001). Os pacientes com maiores níveis de AGL tiveram maior trigliceridemia (196±105 vs 153±81 mg/dl; p < 0,01) e atividade de LCAT (1,36±0,10 vs 1,29±0,10 470/390nm; p < 0,01), além de uma maior concentração de triglicerídeos na partícula de HDL (9,4±2,9 vs 7,8±2,0%; p < 0,001), em relação aos pacientes com menores níveis de AGL. A transferência dos quatro lipídios da nanoemulsão para a HDL foi igual na comparação de todos os grupos deste estudo. Conclusão:Os resultados deste estudo mostraram pela primeira vez que junto com os triglicerídeos, o colesterol não esterificado é também um marcador de pobre controle glicêmico em pacientes com DM2Introduction:One cause of cardiovascular disease (CVD) of patients with type 2 diabetes mellitus (T2DM) is diabetic dyslipidemia, characterized primarily by hypertriglyceridemia and low HDL-cholesterol. Good blood glucose control usually results in decreased plasma triglycerides, but there is controversy in the literature as to the levels of HDL-cholesterol and other lipid parameters. Lipid transfers to HDL play an important role in the formation and remodeling of HDL and on its antiatherogenic role of reverse cholesterol transport. The transfer of lipids between lipoproteins is bidirectional and depends on the structure and concentration of the donor and acceptor lipoprotein as well as the action of the transfers proteins, PLTP and CETP. Objective:Investigate the relationship of blood glucose levels with lipid transfers to HDL and other parameters of lipid metabolism in patients with T2DM. Methods:143 patients with T2DM, who were not using lipid-lowering drugs, were selected and divided into two groups: group with glycated hemoglobin (HbA1c) <= 6.5% (n=62) and group with HbA1c > 6.5% (n=81). In vitro lipid transfers to HDL was performed by 1 hour incubation under stirring of a donor nanoemulsion containing radioactively labeled unesterified and esterified cholesterol, phospholipids and triglycerides with whole patient plasma, followed by chemical precipitation and counting of radiolabeled lipids transferred to HDL. Other determinations of plasma lipid metabolism were also performed. It was also checked the percentage of patients in both groups with lipid profile within the targets set by the American Diabetes Association criteria. Patients with or without insulin use and with higher and lower free fatty acids (FFA) levels were also compared for the studied parameters. Results:HbA1c>6.5% group had higher triglyceridemia (205 ± 115 vs 140 ± 54 mg/dl, p<0.0001) and unesterified cholesterol (36.4 ± 7.6 vs 33.7 ± 5.7 mg/dl, p<0.05) than the HbA1c<=6.5% group. The concentrations of triglycerides, total and unesterified cholesterol and also non-HDL cholesterol was positively correlated with HbA1c (r=0.25, r=0.19, r=0.18, r=0.17, respectively, p<0,05). The concentration of esterified cholesterol from HDL was negatively correlated with HbA1c (r = -0.19, p<0.05). Patients with HbA1c<=6,5% achieved more the triglyceridemic target than the patients with HbA1c>6.5% (66 vs 37%, p<0.001). Patients with higher levels of FFA had higher triglycerides levels (196 ± 105 vs 153 ± 81 mg/dl, P<0.01) and LCAT activity (1.36 ± 0.10 vs 1.29 ± 0.10 470/390nm, p<0.01), in addition to a higher concentration of triglycerides in the HDL particle (9.4 ± 2.9 vs 7.8 ± 2.0%, p <0.001). The transfer of the four lipid of the nanoemulsion to HDL was equal in the comparison of all the studied groups. Conclusion:The results of this study showed for the first time that unesterified cholesterol, along with triglycerides, is also a marker of poor glycemic control in patients with T2DM
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Bedford, Stephen James. "Calculus of variations and its application to liquid crystals". Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:a2004679-5644-485c-bd35-544448f53f6a.
Testo completoAbstract (sommario):
The thesis concerns the mathematical study of the calculus of variations and its application to liquid crystals. In the first chapter we examine vectorial problems in the calculus of variations with an additional pointwise constraint so that any admissible function n ε W1,1(ΩM), and M is a manifold of suitable regularity. We formulate necessary and sufficient conditions for any given state n to be a strong or weak local minimiser of I. This is achieved using a nearest point projection mapping in order to use the more classical results which apply in the absence of a constraint. In the subsequent chapters we study various static continuum theories of liquid crystals. More specifically we look to explain a particular cholesteric fingerprint pattern observed by HP Labs. We begin in Chapter 2 by focusing on a specific cholesteric liquid crystal problem using the theory originally derived by Oseen and Frank. We find the global minimisers for general elastic constants amongst admissible functions which only depend on a single variable. Using the one-constant approximation for the Oseen-Frank free energy, we then show that these states are global minimisers of the three-dimensional problem if the pitch of the cholesteric liquid crystal is sufficiently long. Chapter 3 concerns the application of the results from the first chapter to the situations investigated in the second. The local stability of the one-dimensional states are quantified, analytically and numerically, and in doing so we unearth potential shortcomings of the classical Oseen-Frank theory. In Chapter 4, we ascertain some equivalence results between the continuum theories of Oseen and Frank, Ericksen, and Landau and de Gennes. We do so by proving lifting results, building on the work of Ball and Zarnescu, which relate the regularity of line and vector fields. The results prove to be interesting as they show that for a director theory to respect the head to tail symmetry of the liquid crystal molecules, the appropriate function space for the director field is S BV2 (Ω,S2,/sup>). We take this idea and in the final chapter we propose a mathematical model of liquid crystals based upon the Oseen-Frank free energy but using special functions of bounded variation. We establish the existence of a minimiser, forms of the Euler-Lagrange equation, and find solutions of the Euler-Lagrange equation in some simple cases. Finally we use our proposed model to re-examine the same problems from Chapter 2. By doing so we extend the analysis we were able to achieve using Sobolev spaces and predict the existence of multi-dimensional minimisers consistent with the known experimental properties of high-chirality cholesteric liquid crystals.
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Potiron, Aline. "Conversion du cholestérol en coprostanol par les bactéries du microbiote intestinal humain et impact sur la cholestérolémie". Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLA036/document.
Testo completoAbstract (sommario):
La réduction du taux de cholestérol (CH) sanguin est un point clé dans la lutte contre les maladies cardiovasculaires. L’efficacité contrastée des médicaments disponibles actuellement ainsi que l’intérêt porté autour du microbiote intestinal dans la régulation de la physiologie de l’hôte nous amènent à envisager cette voie comme alternative thérapeutique. La production de coprostanol (CO), dérivé très peu absorbé du CH, par des bactéries de ce microbiote a été corrélée positivement à une faible cholestérolémie. Les objectifs de cette thèse sont i) d’isoler et d’identifier de nouvelles souches bactériennes ayant cette activité, ii) d’identifier les gènes bactériens responsables de cette transformation et iii) de détereminer l’impact de ce métabolisme sur la physiologie de l’hôte. Nous avons isolé 22 nouvelles souches productrices de CO à partir des selles d’un individu en produisant beaucoup. Nous avons choisi les souches Bacteroides sp. D8 et Bacteroides sp. BV pour la construction de deux banques génomiques et huit autres pour des essais d’implantation in vivo dans le tractus gastro-intestinal (TGI) de souris axéniques. Nous avons identifié 55 clones potentiellement positifs par le criblage fonctionnel des banques génomiques. Leurs analyses supplémentaires devraient nous apporter des informations sur les gènes impliqués dans cette activité. Toutes les bactéries sélectionnées sont capables de coloniser le TGI de la souris axénique. La souche Parabacteroides distasonis est la meilleure souche productrice de CO in vivo. Nous avons testé son effet sur la cholestéolémie chez des souris axéniques soumises à un régime riche en CH sur 11 semaines en comparaison avec une souche non productrice in vitro, B. dorei, et avec des souris conventionnalisées comme contrôle. La souche B. dorei produit du CO in vivo, soulignant l’importance de l’environnement dans l’activité de production de CO déjà supposée d’après la littérature et nos résultats in vitro. Des gènes impliqués dans l’excrétion du CH de l’organisme vers les selles sont surexprimés chez ces souris et celles colonisées avec P. distasonis. Cependant seules ces dernières présentent une cholestérolémie plus faible que les souris conventionnalisées. Le mécanisme impliqué semble indépendant de la production de CO et de l’excrétion de CH car les mêmes quantités de ces composés sont retrouvées dans les selles indépendamment du statut bactérien. Les concentrations en acides biliaires totaux dans la bile et dans les selles sont supérieures pour les souris monocolonisées comparées au conventionnalisées. Les selles des souris colonisées avec P. distasonis présentent plus d’acides urso- et chénodésoxycholiques que les souris conventionnalisées et plus d’acide cholique que les souris colonisées avec B. dorei. En conclusion, nous avons isolé de nouvelles souches et identifier des clones potentiellement positifs. Les études in vivo tendent à montrer que l’activité de production de coprostanol n’a pas d’effet sur la cholestérolémie. En revanche, la souche P. distasonis semble diminuer la cholestérolémie par un mécanisme encore inconnuCholesterol (CH) level management is a keystone to limit cardiovascular diseases. The contrasted efficiency of the drugs currently available as well as the interest around the intestinal microbiota in regulating the host physiology lead us to consider this pathway as a therapeutic alternative. The production of coprostanol (CO), a very poorly absorbed CH derivative, by bacteria of this microbiota has been positively correlated with low CH plasma level. The aims of this thesis are (i) isolate and identify new bacterial strains possessing this activity, (ii) identify the bacterial genes responsible for this transformation and (iii) determine the impact of this metabolism on host physiology. We isolated 22 new strains producing CO from the stools of a high-coprostanol producing individual. We chose Bacteroides sp. D8 and Bacteroides sp. BV for the construction of two genomic libraries and eight others for in vivo implantation tests in the gastrointestinal tract (GIT) of germ-free mice. We identified 55 potentially positive clones by functional screening of these genomic libraries. Their additional analyzes should provide us with information about the genes involved in this activity. All selected bacteria are capable of colonizing the GIT of germ-free mice. Parabacteroides distasonis is the best strain producing CO in vivo. We tested its effect on blood cholesterol level in germ-free mice subjected to an 11-week CH-rich diet compared to an in vitro non-producing strain, B. dorei, and with conventionalized mice as control. The B. dorei strain produces CO in vivo, emphasizing the importance of the environment in the CO production activity already assumed from the literature and our results in vitro. Genes involved in the excretion of CH from body to feces are overexpressed in these mice and those colonized with P. distasonis. However, only the latter have lower cholesterolemia than conventional mice. The mechanism involved appears to be independent of CO production and CH excretion because the same amounts of these compounds are found in feces independently of bacterial status. Total biliary acids concentrations in bile and feces are higher for monocolonized mice compared to conventionalized mice. The feces of mice colonized with P. distasonis exhibited more urso- and chenodeoxycholic acids than conventionalized mice and more cholic acid than mice colonized with B. dorei. In conclusion, we have isolated new strains and identified potentially positive clones. In vivo studies tend to show that coprostanol production activity has no effect on plasma cholesterol. In contrast, P. distasonis seems to decrease plasma cholesterol by a still unknown mechanism
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Ben, Hassen Celine. "Cibler l'homéostasie du cholestérol cellulaire pour traiter le cancer du sein". Thesis, Tours, 2019. http://www.theses.fr/2019TOUR3809.
Testo completoAbstract (sommario):
Une femme sur huit sera touchée dans sa vie par le cancer du sein. Les facteurs de risque peuvent être héréditaires et environnementaux. Des études antérieures ont montré que les taux de cholestérol cellulaire peuvent jouer un rôle important dans la régulation de la progression tumorale. Pour confirmer cette hypothèse, nous avons modulé le métabolisme du cholestérol dans les cellules cancéreuses mammaires humaines MCF-7 et MDA-MB-231 en utilisant des approches génétiques : augmentation de l’élimination du cholestérol par l’expression de l’apolipoprotéine A-I (apoA-I, régulant la sortie du cholestérol des cellules) ou modulation du métabolisme du cholestérol par l’expression de l’apolipoprotéine E (apoE, pouvant réguler l’entrée ou la sortie du cholestérol des cellules). Nos expériences ont été menées in vitro et in vivo. Nos résultats montrent que l’expression de l’apoA-I ou de l’apoE stimule la prolifération, la migration, l’invasion et la croissance tumorale des cellules MCF-7 via les voies de signalisation PI3K/AKT et MAPK et possiblement la cavéoline-1. En revanche, l’apoA-I et l’apoE ralentissent la prolifération et la migration des cellules MDA-MB-231One in eight women will have to face breast cancer at some point in her life. Risk factors can be hereditary or environmental. Previous studies have shown that cholesterol levels can play an important role in the regulation of tumor progression. To test this hypothesis, we modulated cholesterol metabolism in human breast cancer cell lines MCF-7 and MDA-MB-231 using a genetics approach: increasing cholesterol elimination by expressing apolipoprotein A-I (apoA-I; regulating cellular cholesterol efflux), or modulating cholesterol metabolism by expressing apolipoprotein E (apoE; regulating cellular influx and efflux of cholesterol). We performed in vitro and in vivo experiments. Our results show that expressing apoA-I or apoE stimulates proliferation, migration, invasion, and tumor growth of MCF-7 cells, via the regulation of the PI3K/AKT and MAPK signaling pathways and possibly via caveolin-1. However, apoA-I and apoE reduce proliferation and migration of MDA-MB-231 cells
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Lai, Wei-An, e 賴薇安. "Beyond cholesterol homeostatic control—how ovarian granulosa cells acquire cholesterol for active steroidogenesis". Thesis, 2013. http://ndltd.ncl.edu.tw/handle/54418390690068318798.
Testo completoAbstract (sommario):
博士國立陽明大學
生理學研究所
101
Ovarian granulosa cells are the major producer of female sex steroids progesterone and estrogen. Granulosa cells synthesize progesterone from the steroid precursor cholesterol, whereas estrogen is produced through aromatase catalysis of theca cell-derived androgen. Ovarian local factor TGFbeta1 facilitates the action of pituitary hormone FSH to promote granulosa cell steroidogenesis. It is known that in non-steroidogenic cells, cellular cholesterol is under homeostatic control involving feedback inhibition of HMG-CoA reductase (key enzyme for cholesterol de novo synthesis) and LDLR (receptor for LDL uptake), while steroidogenic cells additionally express the HDL receptor SR-BI. There are two objectives in this study. The first objective was to investigate how FSH and TGFbeta1 regulate HMG-CoA reductase, LDLR, and SR-BI in granulosa cells. This includes their 1) expression and functional involvement in steroidogenesis, and 2) responsiveness to sterol challenge and identification of potential transcription regulators. We have recently identified that FSH and TGFbeta1 induce calcineurin-dependent activation of CREB coactivator CRTC2 to upregulate steroidogenic gene expression. The second objective was to investigate how calcineurin and CRTC2 are involved in FSH and TGFbeta1 stimulation of estrogen synthesis through controlling aromatase gene (Cyp19a1) expression. Primary culture of granulosa cells from ovarian antral follicles of gonadotropin-primed immature rats was used. HMG-CoA reductase inhibitor simvastatin suppressed the basal and FSH±TGFbeta1-stimulated progesterone synthesis, and additionally, treatment with FSH+TGFbeta1 increased HMG-CoA reductase mRNA and protein level, suggesting the involvement of cholesterol de novo synthesis during steroid synthesis in granulosa cells. Moreover, TGFbeta1 potentiated FSH to upregulate SR-BI and LDLR, and both are functional in uptaking cholesterol as hHDL3 and hLDL supplementation enhanced progesterone production, and the effect of each lipoprotein was completely or partially blocked by SR-BI selective inhibitor BLT-1. Uptaken cholesterol could also be stored in lipid droplets, and this was evidenced by utilization of the fluorescent dye BODIPY 493/503 that stains for neutral lipid. Importantly, LDLR and SR-BI responded to sterol with different sensitivity. Giving cells lipoproteins or 25-hydroxycholesterol downregulated Ldlr but not Scarb1; Scarb1 was ultimately downregulated by excessive sterol accumulation under 25-hydroxycholesterol and aminoglutethimide (inhibitor of steroidogenesis) cotreatment. Finally, ChIP analysis indicated that transcription factors SREBP-2 and LRH-1 crucially mediate Ldlr and Scarb1 differential response to sterol challenge. Next, we asked whether FSH and TGFbeta1 regulate Cyp19a1 through calcineurin and CRTC2. We first observed FSH increased aromatase protein at 24 h which subsided by 48 h, while FSH+TGFbeta1 exerted a greater and longer effect. Further, pretreatment with calcineurin inhibitor (CNI) abolished the FSH+TGFbeta1- but not FSH-upregulated aromatase activity at 48 h, and corresponding changes of Cyp19a1 mRNA was observed at 24 h. Ovary-specific Cyp19a1 PII-promoter contains crucial response elements for CREB and nuclear receptors LRH-1/NR5A2 and SF-1/NR5A1, and Nr5a2 promoter has a CREB-binding site. Chromatin immunoprecipitation analysis revealed FSH and TGFbeta1 increased CRTC2 binding to Cyp19a1 PII-promoter and Nr5a2 promoter at 24 h post-treatment (control < FSH < FSH+TGFbeta1), while CREB was constitutively bound. Simultaneously, FSH+TGFbeta1 but not FSH alone increased the expression of LRH-1 and SF-1 and their binding to Cyp19a1 PII-promoter, and expression of both was suppressed by CNI. These results implicate that calcium-dependent calcineurin importantly mediates FSH and TGFbeta1 upregulation of Cyp19a1, acting directly through CRTC2 to enhance CREB transcriptional activity, and indirectly through upregulation of NR5As. In conclusion, this thesis study first uncovers that ovarian granulosa cells are capable of de novo synthesizing cholesterol and retain the cholesterol homeostatic control machinery like non-steroidogenic cells, while during active steroidogenesis utilize SR-BI to evade such feedback control. Secondly, calcineurin and CRTC2 are critically involved in FSH and TGFbeta1 upregulation of Cyp19a1 transcription for estrogen synthesis. Remarkably, the NR5A nuclear receptors play important regulatory roles in both events.
29
Lee, Chia-Chun, e 李家淳. "Control over the self-assembled ordered nanostructures of phospholipids by incorporation of cholesterol". Thesis, 2017. http://ndltd.ncl.edu.tw/handle/j6w4af.
Testo completoAbstract (sommario):
碩士國立臺灣大學
高分子科學與工程學研究所
105
The interactions between cholesterol and phospholipids have been extensively studied in the aqueous systems. It has been known that the presence of cholesterol can stabilize the cell membrane by inhibiting the movement of hydrocarbon chains. In this study, instead of the self-assembly in aqueous solutions, we probed the impact of cholesterol on the ordered microphase separated structures between the hydrophilic headgroups and the hydrophobic tails of phospholipids in thin film and bulk state. Four phospholipids with varying number of double bonds on the hydrocarbon tails were investigated, including Soy PC, DOPC, Egg PC and DPPC. We utilized atomic force microscopy (AFM) and small-angle X-ray scattering techniques (SAXS and GISAXS) to analyze the structures of phospholipid/cholesterol mixtures and found the structures of the mixtures is highly dependent on the number of double bonds. By changing the fraction of cholesterol, Egg PC with one double bond can phase separate into a variety of regular structures, including spherical, cylindrical and lamellar microdomains, while Soy PC and DOPC with multiple double bonds form spheres and cylinders, and DPPC with no double bond forms lamellae only. We used Fourier transform infrared (FTIR) spectrometer to evidence that cholesterol inserts into phospholipids and form hydrogen bonding with the phosphate on the headgroup. The differential scanning calorimetry (DSC) measurements show that the incorporation of cholesterol into phospholipids significantly affects the thermal behaviors of phospholipids, confirming the interactions between cholesterol and the phospholipids. The domain sizes of the spheres, cylinders, and lamellae formed by the phospholipid/cholesterol mixtures are less than 4 nm, so small that typical block copolymers are unable to reach. The systems developed in this work could be potential for applications such as new templates for fabrication of nanomaterials.
30
Moutinho, Miguel Alves da Silva de Carvalho 1986. "Control of neuronal signalling pathways by CYP46A1, an enzime involved in brain cholesterol homeostasis". Doctoral thesis, 2016. http://hdl.handle.net/10451/23976.
Testo completoAbstract (sommario):
Tese de doutoramento, Farmácia (Biologia Celular e Molecular), Universidade de Lisboa, Faculdade de Farmácia, 2016Cholesterol is an essential molecule in central nervous system physiology and cell signalling, with a wide range of roles, such as being an essential component of cell membranes, lipid rafts and myelin sheets, or serving as a precursor for neurosteroids. The brain relies mainly on de novo cholesterol synthesis and eliminates cholesterol through its conversion to 24(S)-hydroxycholesterol (24OHC), which readily crosses the blood brain barrier into circulation. The enzyme that catalyzes this reaction is the neuronal-specific cholesterol 24-hydroxylase (CYP46A1). Knockout-mice for Cyp46a1 exhibit inactivation of brain cholesterol synthesis, which is accompanied by deficiencies in learning and memory. It has been suggested that the cognitive deficits might be due to a reduction in the levels of intermediaries of the mevalonate pathway, namely isoprenoids. However, it has never been shown if modulation of CYP46A1 expression could effectively affect prenylation, a post-translation modification critical for membrane association of signalling proteins with fundamental roles in cell biology, such as small guanosine triphosphate-binding proteins (sGTPases). Hence, we started by assessing the effect of CYP46A1 expression on the activation of sGTPses in neuronal cells. We observed that increased expression of CYP46A1 enhanced prenylation and activation of sGTPases of the Rho and Rab family, and that this effect was dependent on the activation of the mevalonate pathway. Since sGTPases control a wide variety of functions in the cell, a great number of cellular pathways might be modulated by CYP46A1. Indeed, we have shown that CYP46A1 overexpression leads to a decrease in Liver X Receptor (LXR) transcriptional activity and in mRNA levels of LXR-target genes involved in cholesterol efflux, in a prenylation-dependent manner. These results highlight a novel regulatory axis in neurons; under conditions of membrane cholesterol reduction by increased CYP46A1 expression, neurons enhance isoprenoid synthesis and sGTPase prenylation. Moreover our results also showed that CYP46A1 triggers an increase in neuronal dendritic outgrowth and dendritic protrusion density, and elicits in vitro and in vivo increase of synaptic proteins in crude synaptosomal fractions. Strikingly, in neurons, these effects were abolished by pharmacological inhibition of geranylgeranyl transferase I (GGTase-I) activity. Furthermore, CYP46A1 expression increased tropomyosin-related kinase (Trk) receptors phosphorylation, its interaction with GGTase-I, and the activity of GGTase-I. This interaction Trk-GGTase-I was shown to be crucial for the enhanced dendritic outgrowth mediated by CYP46A1. Cholesterol supplementation studies indicated that cholesterol reduction by CYP46A1 is the necessary trigger for these effects. Taking into account the role of CYP46A1 in cholesterol elimination and neuronal function, we hypothesized that it could be a potential therapeutic target in Niemann-Pick type C disease (NPC), a lysosomal storage disorder, characterized by cholesterol accumulation in the late endosomes/lysosomes (LE/L) compartment, leading to progressive neurodegeneration. Upon ectopic expression of CYP46A1 in human NPC fibroblasts, we observed a reduction in cholesterol accumulation in the LE/L compartment, which was accompanied by partial normalization of the expression levels of several genes involved in cholesterol homeostasis. We used the chemical compound U18666A to mimic the NPC phenotype in neuronal cells, and observed that CYP46A1 overexpression protects and reverts cholesterol accumulation induced by U18666A, but also inhibits the increase in reactive oxygen species and lipid peroxidation. Further experiments led us to conclude that CYP46A1 induces the expression of the antioxidant enzyme heme-oxygenase-1 (HO-1), and that the activity of this enzyme contributes to CYP46A1-mediated protection against oxidative stress. This work contributes to a further understanding of how cholesterol influences the brain, namely how the cholesterol-metabolizing enzyme, cholesterol 24S-hydroxylase affects neuronal development and function, and highlights the role of this enzyme as a therapeutic target in NPC, a disorder that has very limited therapeutic options.
31
Deng-Juin e 林登圳. "The impact of health education on kidney patients’ blood pressure, FPG, creatinine, total cholesterol, and eGFR: a case control study". Thesis, 2010. http://ndltd.ncl.edu.tw/handle/99598232903729861956.
Testo completoAbstract (sommario):
博士中山醫學大學
醫學研究所
98
Background: Taiwan has the highest incidence of dialysis population. Since patients’ education has been demonstrated to be a useful tool to level down the progresses of significant to reduce the deterioration of kidney disease. In this study, researches were performed using those patients whose eGFR is lower than 60/mL/min/1.73m2 to determine the impact of health education on their disease parameters including blood pressure, fasting plasma glucose (FPG),creatinine and eGFR. Methods: This was a quasi-experimental study. A total of 223 patients, whose eGFR is lower than 60/mL/min/1.73m2, were enrolled into this study. Among them, 179 cases received a 2-year of health education, and neither of the rest of the 44 of selected subjects received any education intervention were served as controls in this research. All these patients’ blood pressure, FPG, creatinine and eGFR were measured and data were analyzed. Results: The parameters including systolic pressure, diastolic pressure, FPG and creatinine in those patients received education were significantly decreased when compared them with those controls. However, total cholesterol and eGFR were increased significantly. When further characterized the affects of education intervention by different eGFR levels, the results showed that systolic pressure, diastolic pressure, FPG, total cholesterol and eGFR were reduced significantly in patients with an eGFR higher than 55/mL/min/1.73m2, only systolic pressure were improve in patients with an eGFR between 45 to 55/mL/min/1.73m2, and creatinine and eGFR were meliorated in patients with an eGFR lower than 45/mL/min/1.73m2. Conclusions:The results of this study have provided the crucial evidence that health education intervention on high risk group of chronic kidney patients is able to improve their kidney functions. Furthermore, an early health education intervention shows a positive impact on those chronic kidney disease controls.
32
Kranz, Eylath [Verfasser]. "Dietary habits and life style in the etiology of cholesterol gallstone disease : a matched case control study / vorgelegt von Eylath Kranz". 2002. http://d-nb.info/968492649/34.
Testo completo
33
Chang, Wei-lun, e 張瑋倫. "The Optical Properties of The Cholesteric Liquid Crystal with The Change of It’s Pitch by The Optical Control Method". Thesis, 2008. http://ndltd.ncl.edu.tw/handle/82977472521071036428.
Testo completoAbstract (sommario):
碩士國立臺灣科技大學
高分子系
96
In this study, Cholesteric liquid crystals were prepared by mixing a nematic liquid crystal (E7),a chiral compound (S811).Cholesteric liquid crystals (Ch LCs) have a helical structure, and selectively reflect light of a wavelength proportional to the helical pitch(p).Dissolving a chiral compound in a nematic LC provides a helical structure corresponding to the concentration of chiral compounds dissolved in the nematic LC. We observe what difference in helical pitch and phase transition temperature depend on the concentration of chiral compounds. Cholesteric liquid crystals was doped with azo-dye(DR1). After Ar+ laser irradiation, Optical isomerization of the dye molecules induced change of lical pitch and selectively reflect light of wavelength.