Relevant bibliographies by topics / LDLrKO

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Academic literature on the topic 'LDLrKO'

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Published: 1 February 2025

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Journal articles on the topic "LDLrKO"

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Dupasquier, Chantal M. C., Elena Dibrov, Annette L. Kneesh, Paul K. M. Cheung, Kaitlin G. Y. Lee, Helen K. Alexander, Behzad K. Yeganeh, Mohammed H. Moghadasian, and Grant N. Pierce. "Dietary flaxseed inhibits atherosclerosis in the LDL receptor-deficient mouse in part through antiproliferative and anti-inflammatory actions." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 4 (October 2007): H2394—H2402. http://dx.doi.org/10.1152/ajpheart.01104.2006.

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Dietary flaxseed has been shown to have potent antiatherogenic effects in rabbits. The purpose of the present study was to investigate the antiatherogenic capacity of flaxseed in an animal model that more closely represents the human atherosclerotic condition, the LDL receptor-deficient mouse (LDLrKO), and to identify the cellular mechanisms for these effects. LDLrKO mice were administered a regular diet (RG), a 10% flaxseed-supplemented diet (FX), or an atherogenic diet containing 2% cholesterol alone (CH) or supplemented with 10% flaxseed (CF), 5% flaxseed (CF5), 1% flaxseed (CF1), or 5% coconut oil (CS) for 24 wk. LDLrKO mice fed a cholesterol-supplemented diet exhibited a rise in plasma cholesterol without a change in triglycerides and an increase in atherosclerotic plaque formation. The CS mice exhibited elevated levels of plasma cholesterol, triglycerides, and saturated fatty acids and an increase in plaque development. Supplementation of the cholesterol-enriched diet with 10% (wt/wt) ground flaxseed lowered plasma cholesterol and saturated fatty acids, increased plasma ALA, and inhibited plaque formation in the aorta and aortic sinus compared with mice fed a diet supplemented with only dietary cholesterol. The expression of proliferating cell nuclear antigen (PCNA) and the inflammatory markers IL-6, mac-3, and VCAM-1 was increased in aortic tissue from CH and CS mice. This expression was significantly reduced or normalized when flaxseed was included in the diet. Our results demonstrate that dietary flaxseed can inhibit atherosclerosis in the LDLrKO mouse through a reduction of circulating cholesterol levels and, at a cellular level, via antiproliferative and anti-inflammatory actions.
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Forrest, Lolita M., Elena Boudyguina, Martha D. Wilson, and John S. Parks. "Echium oil reduces atherosclerosis in apoB100-only LDLrKO mice." Atherosclerosis 220, no. 1 (January 2012): 118–21. http://dx.doi.org/10.1016/j.atherosclerosis.2011.10.025.

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Cao, Qiang, Xin Cui, Rui Wu, Lin Zha, Xianfeng Wang, John S. Parks, Liqing Yu, Hang Shi, and Bingzhong Xue. "Myeloid Deletion of α1AMPK Exacerbates Atherosclerosis in LDL Receptor Knockout (LDLRKO) Mice." Diabetes 65, no. 6 (January 28, 2016): 1565–76. http://dx.doi.org/10.2337/db15-0917.

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Bi, Xin, Xuewei Zhu, MyNgan Duong, Elena Y. Boudyguina, Martha D. Wilson, Abraham K. Gebre, and John S. Parks. "Liver ABCA1 Deletion in LDLrKO Mice Does Not Impair Macrophage Reverse Cholesterol Transport or Exacerbate Atherogenesis." Arteriosclerosis, Thrombosis, and Vascular Biology 33, no. 10 (October 2013): 2288–96. http://dx.doi.org/10.1161/atvbaha.112.301110.

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Baumgartner, Roland, Felipe B. Casagrande, Randi B. Mikkelsen, Martin Berg, Konstantinos A. Polyzos, Maria J. Forteza, Aastha Arora, Thue W. Schwartz, Siv A. Hjorth, and Daniel F. J. Ketelhuth. "Disruption of GPR35 Signaling in Bone Marrow-Derived Cells Does Not Influence Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice." Metabolites 11, no. 7 (June 23, 2021): 411. http://dx.doi.org/10.3390/metabo11070411.

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G-protein-coupled receptor-35 (GPR35) has been identified as a receptor for the tryptophan metabolite kynurenic acid (KynA) and suggested to modulate macrophage polarization in metabolic tissues. Whether GPR35 can influence vascular inflammation and atherosclerosis has however never been tested. Lethally irradiated LdlrKO mice were randomized to receive GPR35KO or wild type (WT) bone marrow transplants and fed a high cholesterol diet for eight weeks to develop atherosclerosis. GPR35KO and WT chimeric mice presented no difference in the size of atherosclerotic lesions in the aortic arch (2.37 ± 0.58% vs. 1.95 ± 0.46%, respectively) or in the aortic roots (14.77 ± 3.33% vs. 11.57 ± 2.49%, respectively). In line with these data, no changes in the percentage of VCAM-1+, IAb + cells, and CD3+ T cells, as well as alpha smooth muscle cell actin expression, was observed between groups. Interestingly, the GPR35KO group presented a small but significant increase in CD68+ macrophage infiltration in the plaque. However, in vitro culture experiments using bone marrow-derived macrophages from both groups indicated that GPR35 plays no role in modulating the secretion of major inflammatory cytokines. Our study indicates that GPR35 expression does not play a direct role in macrophage activation, vascular inflammation, and the development of atherosclerosis.
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Schaftenaar, Frank, Jacob Amersfoort, Hidde Douna, Mara Kröner, Bram Slütter, Ilze Bot, Gijs van Puijvelde, and Johan Kuiper. "Vaccination with ApoB100 Derived HLA-A2 Restricted CD8 T Cell Epitopes Did Not Reduce Atherosclerosis in Male LDLrKO hApoB100tg HLA-A2tg Mice." Atherosclerosis Supplements 32 (June 2018): 100–101. http://dx.doi.org/10.1016/j.atherosclerosissup.2018.04.307.

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Jasiecki, Jacek, Monika Targońska, Anna Janaszak-Jasiecka, Magdalena Chmara, Monika Żuk, Leszek Kalinowski, Krzysztof Waleron, and Bartosz Wasąg. "Novel Tools for Comprehensive Functional Analysis of LDLR (Low-Density Lipoprotein Receptor) Variants." International Journal of Molecular Sciences 24, no. 14 (July 14, 2023): 11435. http://dx.doi.org/10.3390/ijms241411435.

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Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused mainly by substitutions in the low-density lipoprotein receptor (LDLR) gene, leading to an increased risk of premature cardiovascular diseases. Tremendous advances in sequencing techniques have resulted in the discovery of more than 3000 variants of the LDLR gene, but not all of them are clinically relevant. Therefore, functional studies of selected variants are needed for their proper classification. Here, a single-cell, kinetic, fluorescent LDL uptake assay was applied for the functional analysis of LDLR variants in a model of an LDLR-deficient human cell line. An LDLR-defective HEK293T cell line was established via a CRISPR/Cas9-mediated luciferase–puromycin knock-in. The expressing vector with the LDLR gene under the control of the regulated promoter and with a reporter gene has been designed to overproduce LDLR variants in the host cell. Moreover, an LDLR promoter–luciferase knock-in reporter system has been created in the human cell line to study transcriptional regulation of the LDLR gene, which can serve as a simple tool for screening and testing new HMG CoA reductase-inhibiting drugs for atherosclerosis therapy. The data presented here demonstrate that the obtained LDLR-deficient human cell line HEK293T-ldlrG1 and the dedicated pTetRedLDLRwt expression vector are valuable tools for studying LDL internalization and functional analysis of LDLR and its genetic variants. Using appropriate equipment, LDL uptake to a single cell can be measured in real time. Moreover, the luciferase gene knock-in downstream of the LDLR promotor allows the study of promoter regulation in response to diverse conditions or drugs. An analysis of four known LDLR variants previously classified as pathogenic and benign was performed to validate the LDLR-expressing system described herein with the dedicated LDLR-deficient human cell line, HEK293T-ldlrG1.
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Strøm, Thea Bismo, Katrine Bjune, Luís Teixeira da Costa, and Trond P. Leren. "Strategies to prevent cleavage of the linker region between ligand-binding repeats 4 and 5 of the LDL receptor." Human Molecular Genetics 28, no. 22 (July 23, 2019): 3734–41. http://dx.doi.org/10.1093/hmg/ddz164.

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Abstract A main strategy for lowering plasma low-density lipoprotein (LDL) cholesterol levels is to increase the number of cell-surface LDL receptors (LDLRs). This can be achieved by increasing the synthesis or preventing the degradation of the LDLR. One mechanism by which an LDLR becomes non-functional is enzymatic cleavage within the 10 residue linker region between ligand-binding repeats 4 and 5. The cleaved LDLR has only three ligand-binding repeats and is unable to bind LDL. In this study, we have performed cell culture experiments to identify strategies to prevent this cleavage. As a part of these studies, we found that Asp193 within the linker region is critical for cleavage to occur. Moreover, both 14-mer synthetic peptides and antibodies directed against the linker region prevented cleavage. As a consequence, more functional LDLRs were observed on the cell surface. The observation that the cleaved LDLR was present in extracts from the human adrenal gland indicates that cleavage of the linker region takes place in vivo. Thus, preventing cleavage of the LDLR by pharmacological measures could represent a novel lipid-lowering strategy.
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Persson, Lena, Cecilia Gälman, Bo Angelin, and Mats Rudling. "Importance of Proprotein Convertase Subtilisin/Kexin Type 9 in the Hormonal and Dietary Regulation of Rat Liver Low-Density Lipoprotein Receptors." Endocrinology 150, no. 3 (November 13, 2008): 1140–46. http://dx.doi.org/10.1210/en.2008-1281.

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Hormonal or dietary challenge can stimulate hepatic low-density lipoprotein receptor (LDLR) expression through posttranscriptional mechanisms. We here tested whether such observations may be due to regulation of proprotein convertase subtilisin/kexin type 9 (PCSK9). Treatment with glucagon resulted in a 2-fold increase in hepatic LDLR protein expression, whereas its mRNA levels were reduced; this occurred simultaneously with a 70% reduction in PCSK9 expression. Insulin treatment resulted in responses opposite to those seen by treatment with glucagon. Furthermore, high-dose ethinylestradiol treatment reduced PCSK9 expression by half. Finally, feeding of rats with dietary cholesterol reduced PCSK9 expression, resulting in an increased number of hepatic LDLRs despite a reduction of LDLR mRNA levels. Regulation of PCSK9 occurred in part through sterol regulatory element binding protein-2, but changes in this cholesterol-controlled transcription factor could not explain all hormonal effects seen. We conclude that the hormonal and dietary regulation of hepatic LDLRs also involves posttranscriptional regulation by PCSK9. The identification of PCSK9 regulation by these various treatments is important in understanding of the physiological function of this protein and points to new targets for therapeutic treatments to increase hepatic LDLR numbers. PCSK9, which reduces LDL-receptors by posttranscriptional mechanisms, is involved in the hormonal stimulation of LDL receptors by glucagon and estrogens.
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Kim, Meewhi, and Ilya Bezprozvanny. "Differences in Recycling of Apolipoprotein E3 and E4—LDL Receptor Complexes—A Mechanistic Hypothesis." International Journal of Molecular Sciences 22, no. 9 (May 10, 2021): 5030. http://dx.doi.org/10.3390/ijms22095030.

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Apolipoprotein E (ApoE) is a protein that plays an important role in the transport of fatty acids and cholesterol and in cellular signaling. On the surface of the cells, ApoE lipoparticles bind to low density lipoprotein receptors (LDLR) that mediate the uptake of the lipids and downstream signaling events. There are three alleles of the human ApoE gene. Presence of ApoE4 allele is a major risk factor for developing Alzheimer’s disease (AD) and other disorders late in life, but the mechanisms responsible for biological differences between different ApoE isoforms are not well understood. We here propose that the differences between ApoE isoforms can be explained by differences in the pH-dependence of the association between ApoE3 and ApoE4 isoforms and LDL-A repeats of LDLR. As a result, the following endocytosis ApoE3-associated LDLRs are recycled back to the plasma membrane but ApoE4-containing LDLR complexes are trapped in late endosomes and targeted for degradation. The proposed mechanism is predicted to lead to a reduction in steady-state surface levels of LDLRs and impaired cellular signaling in ApoE4-expressing cells. We hope that this proposal will stimulate experimental research in this direction that allows the testing of our hypothesis.
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Dissertations / Theses on the topic "LDLrKO"

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Henry, Doriane. "Etude du lien entre la MASLD et l'athérosclérose : implication du récepteur nucléaire PPARα." Electronic Thesis or Diss., Université de Lille (2022-....), 2024. http://www.theses.fr/2024ULILS053.

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Selon l’Organisation Mondiale de la Santé (OMS), les maladies cardiovasculaires (MCV) représentent la première cause de mortalité dans le monde. La prévalence augmentée de la maladie hépatique stéatosique associée à un dysfonctionnement métabolique (MASLD) et sa relation étroite avec le syndrome métabolique laissent suggérer un rôle du foie dans le développement de ces MCV. Cependant, le lien entre MASLD et MCV reste encore peu clair. Dans ce contexte, grâce à l’utilisation d’un modèle murin adapté et de différents outils moléculaires développés au laboratoire, j’ai pu réaliser mes travaux de thèse sur l’exploration du lien entre, d’une part le foie et la MASLD et, d’autre part le développement de l’athérosclérose à l’origine de ces MCV. De plus, le récepteur nucléaire PPARα a été employé comme outil de modulation de la MASLD. Le premier objectif de ma thèse était d’évaluer l’implication du foie dans les effets athéroprotecteurs du pemafibrate, un nouvel agoniste puissant et sélectif de PPARα. Pour cela, nous avons utilisé le modèle de souris double déficient pour le récepteur aux LDL (Ldlr-/-) et pour PPARα, dans lequel l’expression du PPARα sauvage ou d’un mutant de PPARα (exerçant seulement l’activité de transrépression) a été restaurée uniquement dans les hépatocytes de souris grâce à des vecteurs adeno-associated virus (AAV) adaptés. Ces souris ont été soumises à un régime western supplémenté ou non avec le pemafibrate pendant 8 semaines. Les résultats de cette étude montrent que l’activité transrépressive du PPARα hépatocytaire associée aux effets anti-inflammatoires du PPARα dans la MASLD est essentielle et suffisante pour induire les effets athéroprotecteurs du pemafibrate. Le deuxième objectif de ma thèse était de développer un nouveau modèle de souris associant un développement progressif de MASLD et d’athérosclérose dans un contexte cardiométabolique mimant la pathologie humaine. Pour cela, des souris Ldlr-/-, à la fois mâles et femelles, et déficientes ou non en PPARα, ont été soumises à un régime chow ou à un régime enrichi en graisses et en cholestérol. Une cinétique d’évolution de la MASLD et de l’athérosclérose a été réalisée. Les résultats de cette étude montrent un développement progressif à la fois de la MASLD avec toutes les caractéristiques de la pathologie humaine (stéatose, inflammation, ballooning, fibrose) et de l’athérosclérose, dans un contexte pouvant associer obésité et insulinorésistance. De manière intéressante, des spécificités histologiques et métaboliques associées au genre et à la déficience en PPARα ont été observées. Ainsi, les résultats obtenus au cours de ma thèse ont permis de montrer l’importance du foie, et plus particulièrement de l’inflammation hépatique, dans le développement de l’athérosclérose. Le nouveau modèle murin de MASLD et d’athérosclérose permettra de mieux comprendre les mécanismes physiopathologiques mis en jeu dans la MASLD ainsi que les risques cardiovasculaires associés à cette pathologie
According to the World Health Organization (WHO), cardiovascular diseases (CVD) are the leading cause of death in the world. The increased prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and its strong association with metabolic syndrome suggest a role of the liver in the development of CVD. However, the link between MASLD and CVD remains poorly understood. In this context, using an appropriate mouse model and various molecular tools developed in the laboratory, my thesis work explored the link between the liver and MASLD on one hand, and the development of atherosclerosis which leads to CVD, on the other. In addition, the nuclear receptor PPARα was used as a tool to modulate MASLD. The first aim of my thesis was to evaluate the involvement of liver in the atheroprotective effects of pemafibrate, a potent and selective PPARα agonist. To do this, we used a double-knockout mouse model, deficient in both LDL receptor (Ldlr-/-) and PPARα, and restored the expression of wild-type PPARα or a PPARα mutant (exerting only transrepressive activity) specifically in hepatocytes using adeno-associated virus (AAV) vectors. These mice were subjected to a western diet, with or without pemafibrate supplementation, for 8 weeks. The results of this study demonstrated that the transrepressive activity of hepatocyte PPARα, associated with its anti-inflammatory properties, is essential and sufficient to induce the atheroprotective effects of pemafibrate. The second objective of my thesis was to develop a new mouse model able of simultaneously developing progressive MASLD and atherosclerosis in a cardiometabolic context that mimics human pathology. To do this, male and female Ldlr-/- mice expressing (Pparα+/+) or lacking (Pparα-/-) PPARα were fed either a chow diet or a diet enriched in fat and cholesterol. Kinetics of MASLD and atherosclerosis progression were established. The results of this study revealed the progressive development of both MASLD, with all the human characteristics (namely steatosis, inflammation, ballooning and fibrosis), and atherosclerosis in a context that may combine obesity and insulin resistance. Interestingly, histological and metabolic features associated with sex and PPARα-deficiency were observed. In conclusion, the results obtained during my thesis demonstrate the importance of the liver, and more specifically of hepatic inflammation, in the development of atherosclerosis. The new mouse model of MASLD and atherosclerosis will help to better understand the pathophysiological mechanisms involved in MASLD and the cardiovascular risks associated with this pathology
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Wanschel, Amarylis Claudine Bonito Azeredo. "Biodisponibilidade cardiovascular do oxdo nitrico em camundongos LDLr-/-." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314780.

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Orientador: Marta Helena Krieger
Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: O objetivo deste trabalho foi avaliar a biodisponibilidade do óxido nítrico (NOo) nas disfunções cardiovasculares, especificamente na hipertrofia ventricular esquerda e na aterosclerose. Para tanto, realizamos dois estudos em camundongos deficientes do receptor de LDL (LDLr-/-): o primeiro realizado em continuidade aos estudos desenvolvidos anteriormente em nosso grupo de pesquisa, os quais demonstraram a ação do doador de NOo na prevenção da hipertrofia ventricular esquerda e na proteção contra arritmia via indução do acoplamento adrenoceptor-beta2 (ß2AR) à proteína G inibitória (Gi); e no segundo estudo, foi avaliada a biodisponibilidade de NOo na fase inicial da aterogênese, com objetivo de caracterizar as alterações sistêmicas e locais. No primeiro estudo mostramos que o doador de NOo, S-Nitroso-N-acetilcisteína (SNAC) administrado, promoveu ação cardioprotetora contra o remodelamento cardíaco via redução do estresse oxidativo e apoptose celular, os quais foram determinados pelas medidas ventriculares da produção de superóxido (O-o2) e peróxido de hidrogênio (H2O2) e pelo índice de morte celular por apoptose. Esta ação cardioprotetora foi vista no aumento da expressão e no conteúdo de S-nitrosação do ß2AR. Estes efeitos foram associados à cardioproteção contra a arritmia via indução do acoplamento ß2AR à Gi. O objetivo do segundo estudo foi avaliar a biodisponibilidade de NOo na fase inicial da aterogênese em camundongos LDLr-/- no curso temporal de 15 a 60 dias de dieta, com a quantificação de parâmetros sistêmicos representados pela pressão arterial, perfil lipidêmico e ateroma, bem como de parâmetros locais representados pela atividade e expressão da via NO/NOS e suas modificações póstraducionais no processo inflamatório via CD40-CD40L. Camundongos LDLr-/-submetidos à dieta rica em gordura apresentaram progressão do tamanho do ateroma no curso temporal analisado, contudo não foi associado a similares incrementos nos níveis de dislipidemia. Não foram detectadas alterações na pressão arterial do fenótipo hipertenso deste animal. Contudo, localmente foi verificado incremento na atividade da eNOS via fosforilação de resíduos de serina 1179 (S1179) em 30 dias de dieta rica em gordura, que pode ser considerado um mecanismo emergencial à aterosclerose . Posteriormente, com a evolução do ateroma (60 dias) houve redução desta ativação, bem como do conteúdo de proteínas S-nitrosadas. O desenvolvimento de ateroma em 30 e 60 dias induzido pela dieta mostrou aumento da atividade inflamatória por meio da denitrosação de tióis críticos da via CD40. Portanto, a análise das alterações no curso temporal apresentou somente mudanças locais como alteração na biodisponibilidade de NOo, ativação inflamatória via denitrosação do receptor CD40 e redução do conteúdo de S-nitrosação total, enquanto as alterações sistêmicas neste período de tempo ainda não são evidentes
Abstract: The objective of this study was to evaluate the bioavailability of nitric oxide (NOo) in cardiovascular disorders, specifically on the left ventricular hypertrophy and atherosclerosis. Therefore, we performed two studies with LDL receptor-deficient mice (LDLr-/-): the first one was performed in sequence to the studies previously developed in our research group, which showed the NOo donor action on the prevention of left ventricular hypertrophy and protection against arrhythmia via induction of the coupling from beta adrenoceptor-2 (ß2AR) to the inhibitory G protein (Gi); and the second study,it was evaluated the bioavailability of NOo to characterize the systemic and local alterations in the early stages of atherogenesis. The first study showed that the administration of NOo donor S-Nitroso-N-Acetylcysteine (SNAC) promoted cardioprotective action by blocked the cardiac remodeling through reduction of oxidative stress and of apoptosis, which were determined by measures of ventricular superoxide (O-o2) and hydrogen peroxide (H2O2) production and the cell death index, respectively. This cardiprotective action was charactherized by the increase of expression and content of S-nitrosation of ß2AR. These effects were associated with cardioprotection against arrhythimia via induction of ß2AR coupling Gi. The objective of the second study was to evaluate the bioavailability of NOo in the LDLr-/- mice early atherogenesis in LDLr-/ - mice from 15 to 60 days, with the quantification of systemic parameters represented by the blood pressure, lipidemic profile and atheroma as well as local ones represented by the activity and expression of NO/NOS pathway and its post-translational modifications on the inflammatory process via CD40- CD40L. Mice LDLr-/ - maintained on high-fat diet showed progression of atheroma size, although it was not associated with similar increase in dyslipidemic profile. No changes in blood pressure were detected in the hypertensive phenotype of this animal. However, increased activity of eNOS via phosphorylation of Ser1179 (S1179) at 30 days of high-fat diet was detected and it can be considered an emergential mechanism to early atherosclerosis. The development of atheroma (60 days) blocked that activation as well as the protein content of S-nitrosated. The atheroma induced at 30 and 60 days by high-fat diet revealed increase inflammatory activity through denitrosation of critical thiols via CD40. Therefore, the analysis of changes in this time course showed only local changes as changes on NOo bioavailability alteration inflammatory activation via denitrosation of CD40 receptor and the content of total S-nitrosation reduction. However, systemic changes in this period of time have not been evident yet
Doutorado
Fisiologia
Doutor em Biologia Funcional e Molecular
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Nguyen, My-Anh. "Characterization of PCSK9-mediated LDLR Degradation in Hepatic and Fibroblast Cells." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/26114.

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The discovery that proprotein convertase subtilisin/kexin type 9 (PCSK9) mediates degradation of low-density lipoprotein receptors (LDLR) indicates a critical role in LDL metabolism. PCSK9 is a secreted protein that binds to the epidermal growth factor-like (EGF)-A domain of LDLR and directs the receptor for degradation in lysosomes by an unknown mechanism. A gain-of-function mutation, D374Y, increases binding to LDLR EGF-A >10-fold and is associated with a severe form of hypercholesterolemia in humans. Similar to previous studies, data obtained in my project has established that PCSK9 was capable of promoting robust LDLR degradation in liver-derived cell lines; however, minimal effects on LDLR levels were detected in several lines of fibroblast cells despite normal LDLR-dependent cellular uptake of PCSK9. Importantly, a PCSK9 degradation assay showed that 125I-labeled wild-type PCSK9 was internalized and degraded equally in both hepatic and fibroblast cells, indicating dissociation of wild-type PCSK9 from recycling LDLRs in fibroblasts. Moreover, PCSK9 recycling assays confirmed that no recycling of wild-type PCSK9 to the cell surface could be detected in fibroblast cells. In contrast, more than 60% of internalized PCSK9-D374Y recycled to the cell surface in these cells, and thus had reduced ability to direct the LDLR for lysosomal degradation despite persistent binding. Co-localization studies indicated that PCSK9-D374Y trafficked to both lysosomes and recycling compartments in fibroblast cells, whereas wild-type PCSK9 exclusively trafficked to lysosomes. We conclude that two factors diminish PCSK9 activity in fibroblast cells: i) an increased dissociation from the LDLR in early endosomal compartments, and ii) a decreased ability of bound PCSK9 to direct the LDLR to lysosomes for degradation. Finally, an LDLR variant that binds to PCSK9 in a Ca2+-independent manner could partially restore wild-type PCSK9 activity, but not PCSK9-D374Y activity, in fibroblast cells.
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Wanschel, Amarylis Claudine Bonito Azeredo. "Aterogenese em femeas LDLr-/- : efeito da S-nitroso-N-acetilcisteina (SNAC)." [s.n.], 2006. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314556.

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Orientador: Marta Helena Krieger
Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: A incidência de riscos de doença aterosclerótica cardiovascular é maior em homens do que em mulheres na fase reprodutiva, essa diferença diminui quando diminui a produção de estrógenos após a menopausa. Uma série de estudos sugere que essa diferença em ambos os sexos pode ser causada em parte, pela ação pró-aterogênica dos andrógenos. O objetivo deste estudo foi verificar a participação do dimorfismo sexual em camundongos adultos LDLr-/- no efeito vasculoprotetor promovido pelo tratamento com a S-nitrosotiol-N-acetilcisteína (SNAC) na fase inicial da aterogênese por meio dos seguintes avaliações : a) expressão fenotípica da hipertensão; b) desenvolvimento de ateroma; c) perfil lipídico; d) imunorreatividade das isoformas das NOS vasculares. Camundongos machos e fêmeas com 3 meses de idade foram avaliados nos seguintes grupos experimentais: selvagens C57BL/6 (WT) sob dieta comercial; LDLr-/- sob dieta comercial com os controles (CT);LDLr-/-sob dieta hipercolesterolêmica (HC); LDLr-/- sob diet hiperlipidêmica associado ao tratamento com SNAC 0,51µm ip/dia ( HC+SNAC). Após 2 semanas de tratamento com administração de dieta hipercolesterolêmica, verificou-se que as fêmeas desenvolveram lesões ateroscleróticas na aorta proximal ascendente 50% menores em relação aos machos. Tais evidências sugerem o papel protetor do estrógeno presente nas fêmeas adultas no estágio inicial da aterosclerose. O tratamento com SNAC promoveu a redução em 50% na instalação do ateroma em ambos sexos, evidenciando não haver relação com o dimorfismo sexual. Contudo, o perfil lipídico das fêmeas mostrou valores mais elevados que os encontrados em machos, tanto de colesterol (COL), como de triglicérides (TG) plasmáticos nos camundongos sob dieta hipercolesterolêmica. Assim, o tratamento com SNAC não impediu o aumento dos teores lipidêmicos induzidos pela dieta hipercolesterolêmica em fêmeas, inferindo que a condição não está correlacionada ao tamanho da área de lesão desenvolvida. Camundongos fêmeas LDLr-/- sob dieta aterogênica evidenciaram aumento de cerca de 10% na pressão arterial, quando comparados aos respectivos camundongos selvagens (WT). O tratamento com SNAC preveniu totalmente a hipertensão induzida pela dieta hipercolesterolêmica. Contudo, nos machos tal hipertensão foi verificada ocorrer em camundongos LDLr-/- sem dieta hipercolesterolêmica, e o tratamento com SNAC não produziu efeito preventivo na hipertensão. Tais resultados indicam que a gênese da hipertensão é diferente nos dois sexos, sugerindo a participação das vias androgênicas. As fêmeas não apresentaram hipertrofia ventricular esquerda ou redução na frequência cardíaca associada à hipertensão, a qual foi evidenciada nos machos sob as mesmas condições. Assim o conjunto de alterações hemodinâmicas indica que as fêmeas sofreram um menor impacto do que camundongos machos nas alterações cardiovasculares estudadas. A expressão de NOS foi evidenciada na aorta das fêmeas LDLr-/- sob dieta comercial (CT), contudo ausente nas WT e, sob dieta hipercolesterolêmica (HC) a sua imunorreatividade foi menor que no animal controle porém expressiva e difusa , as expressões tanto no controle como no animal HC foram reduzidas pelo tratamento com a SNAC. Estas alterações indicaram a sua participação na disfunção endotelial presente neste modelo e o fato de que o efeito protetor promovido pela SNAC está associado às vias NO/NOS
Abstract: The incidence of risk of coronary artery disease (CAD) is greater in men than in woman during the reproducible years, and this gender difference diminishes after cessation of estrogen production after menopause (Kannel et al, 1976). Many studies have ben suggested also that this gender difference may be caused in part by proaterogenic actions of androgens. The aim this study was verify the role of the sexual dimorphism in LDLr-/- mice in the vasculoprotector effect treatment promoted by S-nitroso-N-acetilcisteína (SNAC) in the initial phase of atherogenesis valuation following:1- phenotypic expression of the hypertension; 2- lesion area development; 3- plasma lipid levels; 4- localization of NOS using immunohistochemistry; Male and female mice 3 months old were evaluated in experimental groups following: C57Bl/6 wild type (WT) chow diet; LDLr-/- control group (CT) chow diet; LDLr-/- hypercholesterolemic diet(HC); LDLr-/- hypercholesterolemic diet plus SNAC 0.51 µmol/Kg ip/daily (SNAC). After treatment for 2 weeks the female developed a 50% decrease lesion area in the proximal aortic as compared to males. This evidence indicated the protector role of the estrogen in female in the initial stage of atherosclerosis. The treatment with SNAC promoted a 50% reduction in installation of atherosclerosis in both sexes with no sexual dimorphism. In female the lesion area was not correlated with the average plasma cholesterol levels. Female mice LDLr-/- under a hypercholesterolemic diet showed an increase of 10% in blood pressure compared whith the background (WT). The treatment with SNAC prevented the hypertension induced by the hypercholesterolemic diet. Nevertheless male hypertension is associated with mice LDLr-/- and chow diet treatment does not prevent hypertension. These results showed that hypertension genesis is different in both sexes suggesting the participation of androgenic pathways. The males showed left ventricular hypertrophy and decreased heart rate associated with hypertension, but the female in the same conditions did not show. Thus is hemodynamic alteration set indicate that female have a less impact than male mice in the studied cardiovascular alterations. The expression of the three types of NOS was evident in aorta of the female LDLr-/- chow diet, although absent in WT. In female LDLr-/- hypercholesterolemic diet there was enhanced immunoreactivity. This overexpression was decreased by treatment with the SNAC. These alterations participated in endothelial dysfunction present in this model and the protector effect promoved by SNAC is associated with the NO/NOS pathways
Mestrado
Fisiologia
Mestre em Biologia Funcional e Molecular
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5

Vasconcelos, Karina Alves da Silva. "Identificação de mutações no gene do receptor da lipoproteína de baixa densidade (LDLR) em pacientes com hipercolesterolemia familiar." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/17/17138/tde-02122015-101322/.

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Hipercolesterolemia familiar (HF) é uma doença autossômica dominante, caracterizada por elevados níveis plasmáticos da lipoproteína de baixa densidade (LDL), desenvolvimento de xantoma tendíneo e arco corneal, além do aumento do risco de doença coronariana e acidente vascular cerebral prematuros. Frequentemente subdiagnosticada, estima-se que apenas 10% dos 400.000 indivíduos com HF no Brasil têm conhecimento da própria doença; afetando, desta forma, a qualidade e a expetativa de vida dos pacientes. Mutações no gene do receptor da LDL (LDLR) são consideradas as alterações genéticas mais frequentes para o desenvolvimento da hipercolesterolemia familiar, pois comprometem a capacidade de remoção das partículas de LDL circulantes, promovendo seu aumento em níveis plasmáticos. Já foram descritas mais de 1600 mutações diferentes no gene LDLR associadas ao fenótipo da HF; entretanto, ainda é difícil determinar em muitas delas o efeito deletério na atividade do receptor. O objetivo desse estudo foi identificar e caracterizar funcionalmente mutações no gene LDLR não descritas na literatura para determinar sua patogenicidade na hipercolesterolemia familiar. Foi avaliada a atividade residual de LDLR através da captação de LDL marcado com fluoróforo lipofílico em cultura de linfócitos T dos pacientes portadores das mutações analisadas após estimulação dos linfócitos T por mitógenos específicos. As mutações Cys82Ser, Thr404Ser, Gly529Arg e His285Tyr foram consideradas patogênicas por acarretarem diminuição da atividade residual do receptor de LDL. As mutações Glu 602X e His388ProfsX53 confirmaram sua patogenicidade e podem ser considerados como controle positivo para futuros ensaios funcionais. Estudos que esclareçam os mecanismos moleculares da HF e da relação genótipo/fenótipo abrem perspectivas para o desenvolvimento de terapias mais específicas na redução dos níveis de colesterol e, consequentemente, da morbidade e mortalidade associadas às doenças cardiovasculares.
Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevated plasma levels of low-density lipoprotein (LDL), and development of corneal arcus tendinous xanthoma, and increased risk of coronary heart disease and premature stroke. Often misdiagnosed, it is estimated that only 10% of the 400.000 patients with FH in Brazil has knowledge of the disease itself, affecting in this way the quality and life expectancy of patients. Mutations in the LDL receptor (LDLR) are considered the most frequent genetic alterations for the development of familial hypercholesterolemia because compromise the ability of removal of circulating LDL particles, promoting its increase in plasma levels. Have been described over 1600 different mutations in the LDLR gene associated with the phenotype of FH, however, it is still difficult to determine in many of the deleterious effects on receptor activity. The aim of this study was to identify mutations in the LDLR gene and functionally characterize mutations not described in the literature to determine its pathogenicity in familial hypercholesterolemia. The residual activity of LDLR was evaluated by raising LDL labeled with lipophilic fluorophore in cultured T lymphocytes of patients with the analyzed mutations after stimulation of T lymphocytes by specific mitogen. The substitution mutations Cys82Ser, Thr404Ser, Gly529Arg e His285Tyr were considered pathogenic because it causes decrease of the residual activity of the LDL receptor in T lymphocytes. The His388ProfsX53 and Glu602X mutations confirmed their pathogenicity and can be considered as positive control for future functional assays. Studies to clarify the molecular mechanisms of HF and genotype/ phenotype open perspectives for the development of more specific therapies for reducing cholesterol levels, and therefore the morbidity and mortality associated with cardiovascular diseases.
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Beehler, Kaitlyn. "MiR-1908 Is a Cholesterol Responsive MicroRNA Implicated In Cholesterol Regulation." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/40422.

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Leveraging miRNA-Seq data and the 1000 Genomes imputed genotypes, we identified rs174561-C as a strong miRQTL for circulating miRNA-1908-5p (P=4.8x10-31) which has an inverse relationship with circulating LDL-C, fasting glucose and A1c. Here I investigated the molecular mechanism(s) linking miR1908-5p to cholesterol metabolism. First, by overexpression experiments in HuH-7 cells demonstrate that the presence of the C allele, associated with lower LDL-C levels, significantly increases miR-1908-5p by 2.15-fold relative to the T allele. Further experiments revealed that 72-hour cholesterol depletion increases miR-1908-5p expression (2.11-fold) whereas cholesterol loading decreases miR-1908-5p expression (0.69-fold). Differential miR-1908-5p expression was then used to profile genes involved in lipoprotein signaling and cholesterol metabolism using a PCR array to identify LDLR as a gene of interest. Although total RNA and protein expression of LDLR was unchanged in response to differential miR-1908-5p expression, the ratio of the mature form to the cleaved form of LDLR decreased following miR-1908-5p inhibition (0.85-fold) and conversely, increased with mimic treatment (1.63-fold). Cleavage of the mature LDLR is known to reduce cell surface affinity for LDL. These findings uncover a potential mechanism linking miR-1908-5p to lower LDL-cholesterol levels through reduced LDLR cleavage.
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Scholtz, C. L. (Charlotte Latitia). "Molecular investigation into regulatory regions of the LDLR gene involved in lipoprotein metabolism." Thesis, Stellenbosch : Stellenbosch University, 2001. http://hdl.handle.net/10019.1/52345.

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Thesis (PhD) -- University of Stellenbosch, 2001.
ENGLISH ABSTRACT: The advent of the new millennium saw the complete sequencing of the entire human genome. Only approximately 30 000 genes, much less than was initially predicted, have been identified to be responsible for the genetic diversity in humans. This discovery has prompted a shift in the approach to disease research, since one gene can be involved in numerous diseases. This phenomenon seems to be especially true for the low-density lipoprotein receptor (LDLR) gene. Various substances beside sterols can induce transcription of the LDLR gene. Non-communicable diseases (e.g. hypertension) are common in the developing world and contribute significantly to mortality rates. The fmding that a promoter variant (-175 g~t) in the LDLR gene is associated with elevated diastolic blood pressure may explain the phenomenon of high LDL-cholesterollevels in hypertensive individuals. Studies have demonstrated that the lowering of cholesterol, especially LDL-cholesterol, can reduce the incidence of hypertension. The -175 g~t variant is located in a newly described cis-acting regulatory element which contains a putative binding site for Yin Yang (YY)-l and also demonstrates great homology to the cAMP response element (CRE) which bind the Ca2+- dependent transcription factor, CRE binding protein (CREB). The fact that Ca2+ can induce transcription of the LDLR gene may, at least in part, explain the association between the - 175g~t variant and elevated diastolic blood pressure. Cholesterol is important for various processes, such as apoptosis, maintenance of cellular membranes and immune function. The -59 c-ot mutation in repeat 2 of the LDLR gene abolishes binding of the sterol regulatory element binding protein(SREBP) to the SRE-l site. SREBP is proteolytically activated during apoptosis by two caspases (CPP32 and Mch3) to induce cholesterol levels. Our results imply that the -59C/T mutation, in repeat 2 of the LDLR gene promoter, may inhibit apoptosis under normal immunological conditions. Atherosclerosis can be considered an immunological disease, since various humoral and cellular immune processes can be detected throughout the course of the disease. The fmding that certain lipoproteins can protect against infection by binding and lysing of pathogens, or competing with pathogens for cellular receptors, prompted the investigation into the potential role of variation in the LDLR gene promoter in immune function. A significant difference in allelic distribution was detected between asymptomatic HIY -infected subjects and fast progressors for the -124 c-ot variant (P=O.006), shown to increase (~160%) transcriptional activity of the LDLR gene. Of relevance to this particular study is the fact that human herpesvirus (HHV) 6 can transactivate CD4 promoters through a partial CRE site. It has been shown that the CREB and YYl can regulate viral and cellular promoters, and these transcription factors can potentially bind to the LDLR promoter at the FP2 site. The mutation enrichment in the LDLR gene promoter seen in the South African Black and Coloured population groups can possibly provide insight into the pathogenesis of various diseases. This could also potentially, provide novel targets for treatment, since manipulation of cholesterol levels may affect the pathogenesis of various diseases.
AFRIKAANSE OPSOMMING: Die volledige DNA volgorde bepaling van die mensgenoom is voltooi vroeg in die nuwe millennium. Slegs ongeveer 30 000 gene is geidentifiseer, heelwat minder as wat in die verlede voorspel is, wat verantwoordelik is vir die genetiese diversiteit in die mens. Hierdie ontdekking het gelei tot 'n verandering in die benadering van navorsing ten opsigte van siektes, aangesien een geen 'n rol by verskeie siektes kan speel. Hierdie gewaarwording blyk veral waar te wees vir die lae digtheids lipoproteien reseptor (LDLR) geen. Verskeie stimuli, buiten sterole, kan transkripie van die LDLR geen inisieer. Verskeie siektes soos hipertensie is algemeen in die ontwikkelende wereld, en dra by tot die hoe mortaliteit syfers. Die bevinding dat 'n promoter variant in die LDLR geen (-175g-H) geassosieer is met verhoogde diastoliese bloeddruk, kan moontlik verhoogde lipiedvlakke in hipertensiewe individue verklaar. Studies het aangetoon dat die verlaging van cholesterol, veral LDL-cholesterol, die voorkorns van hipertensie kan verlaag. Die -175 g~t variant is gelee in 'n cis-regulerende element wat na bewering 'n bindingsetel vir die Yin Yang (YY)-l transkripsie faktor bevat asook sterk homologie met die cAMP respons element (CRE) toon, wat bind aan die Ca2 +_ afhanklike transkripie faktor, CRE bindings proteiene (CREB). Die feit dat Ca2+ transkripsie van die LDLR geen kan inisieer, kan dalk tot 'n mate, 'n verklaring bied vir die assosiasie tussen die -175 (g~t) variant en verhoogde diastoliese bloeddruk. Cholesterol is noodsaaklik vir verskeie prosesse soos apoptose, die instandhouding van selmembrane sowel as immuun funksies. Die -59 c-ot mutasie in die sterol regulerende element 1 (SRE-l) van die LDLR geen vernietig binding van die sterol regulerende element bindingsprotei'en (SREBP) aan SRE-l. SREBP word proteolities geaktiveer tydens apoptose deur twee kaspases (CPP32 en Mch3) om cholesterolvlakke te induseer. Ons resultate impliseer dat die -59C/T mutasie, in herhaling-2 van die LDLR-geen promoter, apoptose kan inhibeer onder normale immunologiese toestande. Aterosklerose kan beskou word as 'n immunologiese siekte, aangesien verskeie humorale en sellulere immuun prosesse deur die verloop van die siekte waargeneem kan word. Die feit dat Iipoproteiene beskermend kan wees teen infeksies, deur binding en lisering van virusse of kompeteer met patogene vir sellulere reseptore, het aanleiding gegee tot 'n ondersoek na die potensiele rol van variasies in die promoter area van die LDLR geen in immuun funksie. Betekenisvolle verskille in alleel verspreiding vir die -124c~t variant (P=0.006) is waargeneem tussen asimptomatiese MIV -geinfekteerde pasiente en individue met vinnige siekte progressie. In vitro studies het voorheen getoon dat die -124c~t 'n verhoging in LDLR geen transkripsie (160%) tot gevolg het. Dit is noemenswaardig dat 'n vroee studie getoon het dat die mens like herpesvirus-6 (MHV6) transaktivering van die CD4 promoters deur 'n gedeeltelike CRE bindingsetel kan bewerkstellig. Beide CREB en YYl kan virus en sellulere promotors reguleer, en hierdie transkripsie faktore toon bindingshomologie met die FP2 element van die LDLR promotor Die mutasie verryking van die LDLR geen promoter soos waargeneem in Suid Afrikaanse Swart en Kleurling populasies, kan moontlik lig werp op die patogenese van verskeie siektetoestande. Hierdie bevindinge kan potensieel nuwe teikens vir behandeling identifiseer, aangesien manipulasie van cholesterolvlakke 'n effek mag he op die patogenese van verskeie siektes.
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Leitch, Eilidh Kathryn. "Identification and development of novel cyclic peptide inhibitors of IDOL mediated LDLR degradation." Thesis, University of Southampton, 2017. https://eprints.soton.ac.uk/417920/.

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Cholesterol is an essential component of the plasma membrane however if present in excess, free cholesterol is toxic to cells and can lead to complications such as atherosclerosis, and ultimately cardiovascular disease. The low density lipoprotein receptor binds and internalises circulating plasma cholesterol, present in low density lipoprotein molecules. The low density lipoprotein receptor has two main transcriptional regulators: liver X receptors and sterol regulatory element binding proteins and post-transcriptional regulators, namely the E3-ubiquitin ligase IDOL, which binds and ubiquitinates the low density lipoprotein receptor intracellular tail, targeting it for lysosomal degradation. Several protein-protein interactions are required for the ubiquitination activity of IDOL, serving as potential therapeutic modulation sites for the treatment of hypercholesterolemia via an upregulation of low density lipoprotein receptor protein levels. Bacterial reverse-two hybrid systems were designed for the IDOL-LDLR heterodimerisation and the IDOL homodimerisation interactions. The latter system was used to screen a library of 3.2 million cyclic peptides, identifying a series of peptides capable of inhibiting the IDOL homodimerisation event. These peptides were synthesised and their activity assessed using a selection of in vitro assays, providing a lead candidate. The efficacy of the lead candidate peptide was improved through the development of a small library of non-natural derivatives, improving binding activity by 7-fold. The activity of the new generation peptide was assessed both in vitro for ability to inhibit autoubiquitination and in hepatic cells, elucidating biological implications of the inhibition of IDOL mediated LDLR degradation.
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9

Werutsky, Carlos Alberto. "As bases moleculares das hipercolesterolemias familiares no Brasil: o Rio Grande do Sul." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/17/17138/tde-01082007-105409/.

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A hipercolesterolemia familiar (HF) é uma doença autossômica dominante causada por mutações no gene do receptor de LDL (LDLR) (cromossomo 19p13.1 - p13.3), que alteram parcialmente ou totalmente a função do LDLR. A HF é também uma das doenças genéticas mais comuns com freqüências estimadas de heterozigotos e homozigotos de 1/500 e 1/1.000.000, respectivamente. Manifesta-se com altos níveis de LDL colesterol, arco corneal, xantomas tendíneos e sintomas prematuros de doença coronariana.. A grande heterogeneidade observada na manifestação clínica desta doença pode ser explicada, ao menos parcialmente, pelo amplo espectro de mutações no gene do LDLR. O presente estudo teve por objetivo a caracterização molecular do gene LDLR em pacientes com HF do Rio Grande do Sul (RS), Brasil. Para isso, foram obtidas amostras de DNA de 40 indivíduos provenientes de cinco macrorregiões do Estado, representando seis diferentes populações de ascendência européia, para a realização do seqüenciamento direto do gene do LDLR, com posterior análise por meio das ferramentas de bioinformática. Quinze mutações pontuais foram identificadas no gene do LDLR, a saber: c.408C>T (D115D), c.1616C>T (P518L), c.1773C>T (N570N) e c.2243A>G (D727G) na região codificadora, IVS6+36G>A, IVS6+171G>A, IVS11+56C>T, IVS11- 69G>T, IVS11-55A>C, IVS15-136A>G, IVS16+46C>T e IVS17-42A>G na região intrônica, e *52G>A, *105T>G e *141G>A na região 3\'-UTR. Destas, oito ainda não foram descritas na literatura (três situadas nos exons, quatro nos introns e uma na região 3\'-UTR). A mutação*52G>A foi previamente identificada em pacientes com HF da região Sudeste do Brasil, sugerindo que possa exercer um importante efeito na patogênese da HF em pacientes brasileiros. Em relação às macrorregiões do RS, os portugueses, italianos e espanhóis apresentaram o maior número de mutações dentre os grupos étnicos analisados. Assim, os resultados obtidos confirmam que existe um amplo de espectro de mutações no gene do LDLR. As mutações nas regiões intrônicas precisam ser investigadas sobre seu efeito potencial no desenvolvimento de HF. Considerando que este é o primeiro estudo que teve por objetivo a caracterização molecular de pacientes com HF no RS, novos estudos que visem a elucidação das bases moleculares da HF devem ser realizados, a fim de obter uma melhor caracterização genética desta doença no Brasil.
Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in the low-density lipoprotein receptor (LDLR) gene (chromosome 19p13.1 - p13.3), which alter partially or totally the LDLR function. FH is also one of the most common inherited disorders with frequencies of heterozygotes and homozygotes estimated to be 1/500 and 1/1.000.000, respectively. Affected individuals display high levels of LDL cholesterol, arcus corneae, tendon xanthomas and premature symptomatic coronary heart disease. The extensive heterogeneity observed in the clinical manifestation of this disorder may be explained, at least partially, by the broad spectrum of mutations identified in the LDLR gene. The present study had as the main goal the molecular characterization of the LDLR gene in patients with FH from Rio Grande do Sul (RS) State, Brazil. For this, DNA samples were obtained from 40 individuals living in five macroregions of RS, representing six different isolated populations of European ascendancy. The LDLR gene was subjected to the direct sequencing with further analysis through bioinformatics tools. Fifteen punctual mutations were identified in the LDLR gene, namely: c.408C>T (D115D), c.1616C>T (P518L), c.1773C>T (N570N) and c.2243A>G (D727G) in the coding region, IVS6+36G>A, IVS6+171G>A, IVS11+56C>T, IVS11-69G>T, IVS11-55A>C, IVS15-136A>G, IVS16+46C>T and IVS17-42A>G in the intronic region, and *52G>A, *105T>G and *141G>A in the 3\'-UTR region. Of these, eight were not yet described in the literature (three situated in exons, four in introns and one in 3\'- UTR region). The *52G>A mutation was previously identified in FH patients from Southeast Brazil, suggesting that it can exert an important effect in the pathogenesis of FH in Brazilian patients. In relation to the macroregions of Rio Grande do Sul, Portuguese, Italian and Spanish subjects carried the highest number of mutations among the ethnic groups analyzed. Thus, the results obtained confirm the existence of a broad spectrum of mutations in the LDLR gene. The mutations in intronic regions need to be investigated in relation to its potential effect in the development of FH. Taking into account that this is the first study that had as the goal the molecular characterization of FH patients in RS, further studies aimed at elucidating the molecular bases of FH should be performed, in order to obtain the better characterization of this disease in Brazil.
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Lin, Jennifer W. "Techniques for identifying long-range residue correlations in the fifth binding module of LDLR." Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/36808.

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Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2006.
Includes bibliographical references (p. 87-90).
The study of correlations between residues in distal regions of a protein structure may provide insights into the mechanism of protein folding. Such long-range correlations may exist between distant residues that are conserved by evolution or physically related by motion. Two computational approaches, one involving hidden Markov models (HMMs) and the other applying molecular dynamics (MD), were implemented to identify a comprehensive set of residue couplings, as well as provide possible explanations for the correlations. HMMs were employed to model the secondary structural elements of proteins in order to discover residues correlated by coevolution. MD simulations and cross-correlation analyses were performed to determine residues coupled by motion. The protein system that was chosen for the study of long-range correlated residues was the fifth binding module (LR5) of the low-density lipoprotein receptor (LDLR) which regulates the cholesterol level in the bloodstream.
(cont.) The LR5 repeat is crucial to the binding of LDLR to lipoprotein particles that carry cholesterol. The HMM and MD approach identified correlations between residues that have been postulated to bind to a particular type of lipoprotein and residues involved in calcium ion coordination which maintains the folding of the LDLR structure. Energetic pathways of the LR5 module were constructed to provide insights into structural stability and functional importance of the residue couplings.
by Jennifer W. Lin.
M.Eng.
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Books on the topic "LDLrKO"

1

Cicmil, Svetlana. Organisational behaviour and change in the context of total quality principles: The LDLR case study. Leicester: Leicester Business School, De Montfort University, 1995.

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Book chapters on the topic "LDLrKO"

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Arroyo, E., C. Asperilla, L. Prieto, M. Herrera, and J. M. Ruiz de la Cuesta. "Frequency Multivariate Analysis of LDLR, GYPA, HBGG, D7S8 and GC in 12 Different Populations." In 16th Congress of the International Society for Forensic Haemogenetics (Internationale Gesellschaft für forensische Hämogenetik e.V.), Santiago de Compostela, 12–16 September 1995, 492–94. Berlin, Heidelberg: Springer Berlin Heidelberg, 1996. http://dx.doi.org/10.1007/978-3-642-80029-0_145.

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Varma, S., A. D. McIntyre, and R. A. Hegele. "Atypical Presentation and Treatment Response in a Child with Familial Hypercholesterolemia Having a Novel LDLR Mutation." In JIMD Reports, 67–70. Berlin, Heidelberg: Springer Berlin Heidelberg, 2016. http://dx.doi.org/10.1007/8904_2016_29.

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Hara, M., A. Kido, K. Saito, A. Takada, K. Yabe, T. Murai, and H. Watanabe. "Allele Frequency Distribution of Five Loci (LDLR, GYPA, HBGG, D7S8 and GC) in a Japanese Population." In 16th Congress of the International Society for Forensic Haemogenetics (Internationale Gesellschaft für forensische Hämogenetik e.V.), Santiago de Compostela, 12–16 September 1995, 544–46. Berlin, Heidelberg: Springer Berlin Heidelberg, 1996. http://dx.doi.org/10.1007/978-3-642-80029-0_164.

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Miścicka-Śliwka, D., K. Śliwka, A. Syroczyńska, T. Grzybowski, B. Baranowska, and J. A. Berent. "Allele Frequencies of D1S80, LDLR, GYPA, D7S8, GC, HBGG and SE 33 in Polish Population Sample." In 16th Congress of the International Society for Forensic Haemogenetics (Internationale Gesellschaft für forensische Hämogenetik e.V.), Santiago de Compostela, 12–16 September 1995, 581–83. Berlin, Heidelberg: Springer Berlin Heidelberg, 1996. http://dx.doi.org/10.1007/978-3-642-80029-0_177.

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Tagliabracci, Adriano, Loredana Buscemi, Nicola Cucurachi, Roberto Mencarelli, Raffaele Giorgetti, and Santo Davide Ferrara. "A Population Study of 5 PCR Genetic Markers, LDLR, GYPA, HBGG, D7S8 and Gc, in Italy." In 16th Congress of the International Society for Forensic Haemogenetics (Internationale Gesellschaft für forensische Hämogenetik e.V.), Santiago de Compostela, 12–16 September 1995, 635–37. Berlin, Heidelberg: Springer Berlin Heidelberg, 1996. http://dx.doi.org/10.1007/978-3-642-80029-0_196.

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Masliah, Eliezer, and Brian Spencer. "Applications of ApoB LDLR-Binding Domain Approach for the Development of CNS-Penetrating Peptides for Alzheimer’s Disease." In Methods in Molecular Biology, 331–37. New York, NY: Springer New York, 2015. http://dx.doi.org/10.1007/978-1-4939-2806-4_21.

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Crespillo, M., J. A. Luque, P. García, E. Ramírez, R. M. Fernández, and J. L. Valverde. "Population Study for the HLA-DQA1, LDLR, GYPA, HBGG, D7S8 and GC Loci in North-East of Spain." In 16th Congress of the International Society for Forensic Haemogenetics (Internationale Gesellschaft für forensische Hämogenetik e.V.), Santiago de Compostela, 12–16 September 1995, 517–19. Berlin, Heidelberg: Springer Berlin Heidelberg, 1996. http://dx.doi.org/10.1007/978-3-642-80029-0_153.

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Herrera, M., C. Asperilla, M. A. Aumente, L. Prieto, E. Arroyo, and J. M. Ruiz de la Cuesta. "Frequency Data on the Loci LDLR, GYPA, HBGG, D7S8 and GC in a population resident in Madrid (Spain)." In 16th Congress of the International Society for Forensic Haemogenetics (Internationale Gesellschaft für forensische Hämogenetik e.V.), Santiago de Compostela, 12–16 September 1995, 547–48. Berlin, Heidelberg: Springer Berlin Heidelberg, 1996. http://dx.doi.org/10.1007/978-3-642-80029-0_165.

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García, O., P. Martín, C. Albarrán, and A. Alonso. "Allele frequencies of HLA-DQA1, LDLR, GYPA, HBGG, D7S8 and GC in the resident population of the Basque Country." In Acta Medicinæ Legalis Vol. XLIV 1994, 41–43. Berlin, Heidelberg: Springer Berlin Heidelberg, 1995. http://dx.doi.org/10.1007/978-3-642-79523-7_11.

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Castillo, M. I., M. Paredes, C. Peñuela, I. Bustos, M. Jimenez, and A. Galindo. "Determination of the Allele and Genotype Frequencies of Loci HLA-DQA1, LDLR, GYPA, HBGG, D7S8 and GC in Bogota-Colombia." In 16th Congress of the International Society for Forensic Haemogenetics (Internationale Gesellschaft für forensische Hämogenetik e.V.), Santiago de Compostela, 12–16 September 1995, 503–5. Berlin, Heidelberg: Springer Berlin Heidelberg, 1996. http://dx.doi.org/10.1007/978-3-642-80029-0_149.

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Conference papers on the topic "LDLrKO"

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Kong, Jeremy, and Alessio Lomuscio. "Model Checking Multi-Agent Systems against LDLK Specifications." In Twenty-Sixth International Joint Conference on Artificial Intelligence. California: International Joint Conferences on Artificial Intelligence Organization, 2017. http://dx.doi.org/10.24963/ijcai.2017/158.

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We define the logic LDLK, a formalism for specifying multi-agent systems. LDLK extends LDL with epistemic modalities, including common knowledge, for reasoning about the evolution of knowledge states of the agents in the system. We study the complexity of verifying a multi-agent system against LDLK specifications and show this to be in PSPACE. We give an algorithm for the practical verification of multi-agent systems specified in LDLK. We show that the model checking algorithm, based on alternating-automata and nFA, is amenable to symbolic implementation on OBDDs. We introduce MCMAS LDLK , an extension of the open-source model checker MCMAS, implementing the algorithm and discuss the experimental results obtained.
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Ly, Kévin, Anna Kwiatkowska, Sophie Routhier, Roxane Desjardins, Monika Lewandowska, Adam Prahl, Josée Hamelin, Nabil G. Seidah, Yves Dory, and Robert Day. "Development of Peptide Inhibitors Disrupting PCSK9-LDLR Protein-Protein Interactions." In The Twenty-Third American and the Sixth International Peptide Symposium. Prompt Scientific Publishing, 2013. http://dx.doi.org/10.17952/23aps.2013.110.

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Larrea Sebal, Asier, Unai Galicia Garcia, Shifa Jebari Benslaiman, Rocio Alonso Estraba, Asier Benito Vicente, Kepa B. Uribe, Sonia Arrasate Gil, Humberto González Díaz, and Cesar Martin Plagaro. "MLb-LDLr: LDLaren hartzaile aldaeren eragina aurresateko ikasketa automatikoko eredua." In IV. Ikergazte. Nazioarteko ikerketa euskaraz. Bilbao: UEU arg, 2021. http://dx.doi.org/10.26876/ikergazte.iv.04.01.

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Gao, Ya, Wenhui Zhang, and Xue-Yang Zhu. "Multi-Agent Automata and Its Application to LDLK Satisfiability Checking." In 2021 IEEE 21st International Conference on Software Quality, Reliability and Security (QRS). IEEE, 2021. http://dx.doi.org/10.1109/qrs54544.2021.00111.

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ПОЛЯКОВА, Е. А., Е. С. ЯКИМЕНКО, А. Д. ПЕРЕЛЯЕВ, М. Д. БУШУЕВА, and А. В. МАЗИНГ. "МУТАЦИЯ В ГЕНЕ LDLR (ГЕТЕРОЗИГОТА) У ПАЦИЕНТКИ С МУЛЬТИФОКАЛЬНЫМ АТЕРОСКЛЕРОЗОМ." In ОЖИРЕНИЕ, САХАРНЫЙ ДИАБЕТ И КОМОРБИДНЫЕ ЗАБОЛЕВАНИЯ. Медиапапир, 2024. http://dx.doi.org/10.52565/9785001104315_102.

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Khuu, MP, K. Kiouptsi, G. Pontarollo, EPC van der Vorst, Y. Döring, M. Müller, K. Schäfer, and C. Reinhardt. "Gut microbiota promotes arterial thrombus formation in hyperlipidemic Ldlr-/- mouse model." In GTH Congress 2023 – 67th Annual Meeting of the Society of Thrombosis and Haemostasis Research – The patient as a benchmark. Georg Thieme Verlag, 2023. http://dx.doi.org/10.1055/s-0042-1760466.

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Tworowska, Izabela, Leo G. Flores II, Rafal Zielinski, Jonathan Nowak, Pascaline Lecorche, Cedric Malicet, Michel Khrestchatisky, Jamal Temsamani, and Ebrahim Delpassand. "Abstract LB-A16: Imaging of glioblastoma using LDLR-based targeted delivery system." In Abstracts: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 26-30, 2019; Boston, MA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1535-7163.targ-19-lb-a16.

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Hoi, Yiemeng, Mark Van Doormaal, Yu-Qing Zhou, Xiaoli Zhang, R. Mark Henkelman, and David A. Steinman. "Degree of Retrograde Flow and Its Effect on Local Hemodynamics and Plaque Distribution in an Aortic Regurgitation Murine Model of Atherosclerosis." In ASME 2011 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2011. http://dx.doi.org/10.1115/sbc2011-53161.

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Previously, Zhou et al. [1] presented a novel mouse model of aortic valve regurgitation (AR) to explore the effect of altered hemodynamics on atherogenesis. In these ldlr−/− mice with AR, extensive atherosclerotic plaque was found along the naturally lesion-free descending thoracic (DTAo) and abdominal aorta (AbAo), with distinct spatial distributions suggestive of a strong local hemodynamic influence (Fig. 1, top). Doppler ultrasound measurement showed that both DTAo and AbAo of the AR mice experienced an oscillatory flow pattern induced by the diastolic retrograde flow, as opposed to the consistent antegrade flow found in the non-AR mice. The study also suggested that the fraction of the DTAo surface covered by lesions tends to increase with the absolute diastolic retrograde Time-Velocity Integral (TVI) as measured from the Doppler ultrasound.
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Etxebarria Gallego, Aitor. "Hiperkolesterolemia familiarra: LDLR, APOB eta PCSK9-en mutazioen balioztapen funtzionala diagnostiko zehatz baterako." In I. Ikergazte. Nazioarteko ikerketa euskaraz. Bilbao: UEU arg, 2015. http://dx.doi.org/10.26876/ikergazte.i.104.

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Мешков, А. Н., А. И. Ершова, А. В. Киселева, Е. Д. Зотова, Е. Сотникова, А. В. Петухова, А. Жарикова, et al. "Спектр вариантов в генах LDLR, APOB и PCSK9 у российских пациентов с семейной гиперхолестеринемией." In Вычислительная биология и искусственный интеллект для персонализированной медицины. Федеральное государственное бюджетное учреждение «Национальный медицинский исследовательский центр эндокринологии» Министерства здравоохранения Российской Федерации, 2021. http://dx.doi.org/10.14341/cbaipm-2021-21.

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