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Author: Monika ‡e author Sharma
Publisher:
ISBN:
Category :
Languages : en
Pages : 200
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Book Description
Lipoprotein(a) (Lp(a)) comprises a low density lipoprotein (LDL) particle with one molecule of apolipoprotein B-100 (apoB-100) and one molecule of apolipoprotein(a) [apo(a)], a protein evolutionary derived from plasminogen. The apo(a) protein consists of two plasminogen kringle domains, kringle IV (KIV) and kringle V (KV). KIV is further divided into 10 subclasses, KIV1-10. Repetition of the KIV2 domain is responsible for the size heterogeneity of apo(a) isoforms. The size of apo(a) isoforms is inversely correlated with plasma Lp(a) levels and elevated levels of Lp(a) (>50 mg/dL) are directly associated with cardiovascular disease risk. Plasma Lp(a) levels and cardiovascular disease risk share a “J” shape relationship where lower plasma Lp(a) levels (50 mg/dL) reduces cardiovascular disease risk compared to those with no Lp(a). However, a proportional increase in cardiovascular disease risk is observed with increasing plasma Lp(a) levels (50 mg/dL). The beneficial effects of having low Lp(a) concentrations occur through an unknown mechanism. A significant positive correlation between Lp(a) and high density lipoprotein cholesterol (HDL-C) is observed in African-American populations and in the multi-ethnic Dallas heart study population, indicative of a biological connection between Lp(a) and HDL-C. Previous studies by our group and by others have also suggested that there is a positive connection between Lp(a) and HDL-C where elevated HDL-C levels were observed in Lp(a) transgenic mice. The first aim of this thesis was to investigate the mechanism responsible for the biological connection between Lp(a) and HDL-C. Plasma HDL-C levels are regulated by the expression of several genes in the liver. The HDL biogenesis pathway is primarily regulated by the ATP-binding cassette A1 (ABCA1), a cholesterol transporter. In this study, the effects of Lp(a) on the HDL biogenesis pathway in a hepatic cellular model (HepG2 cells) were investigated. Interestingly, Lp(a) upregulated ABCA1-mediated cholesterol efflux via the peroxisomal proliferator activated receptor and liver X receptor transcription factors. Further investigations revealed that it was the oxidised phospholipid content of Lp(a) that induced ABCA1 expression. Oxidised phospholipids from Lp(a) were delivered via the scavenger receptor-B1 (SR-B1) to stimulate an ABCA1 response in HepG2 cells. An interesting observation from these results was the internalisation of apo(a), independent of the SR-B1-mediated Lp(a) lipid internalisation. Multiple studies have implicated several receptors in Lp(a) uptake, however the precise receptor and mechanism responsible for Lp(a) clearance from plasma remains unknown. The second aim of this thesis was to characterise the uptake and intracellular trafficking of Lp(a) in HepG2 cells. This study has determined that the endocytosed Lp(a) follows an early endosome to trans-Golgi/recycling endosome trafficking route. This retrograde trafficking of Lp(a) recycles apo(a) into the media where it appears to re-assemble Lp(a). Interestingly, Lp(a) uptake was dependent on L-type calcium channels, suggesting calcium-dependent endocytosis in HepG2 cells. Notably, Lp(a) uptake was independent of proposed Lp(a) receptors, the asialoglycoprotein receptor and the LDL receptor. A preliminary investigation has revealed that the plasminogen receptor, PlgRKT might be responsible for Lp(a) internalisation. After establishing the methods to investigate the HDL synthesis pathway, the effects of chemotherapy drugs on lipid metabolism targets were investigated. This work was motivated by the findings of a colleague of my supervisor who had observed a decrease in HDL-C levels in breast cancer patients undergoing chemotherapy. This lead to the third aim: to investigate the effects of chemotherapy drugs (doxorubicin, cyclophosphamide and paclitaxel) on the HDL biogenesis pathway. Surprisingly, doxorubicin, a common chemotherapy agent, lowered HDL-C in HepG2 cells by decreasing ABCA1-mediated cholesterol efflux. Additionally, paclitaxel (another common chemotherapy agent) increased LDL-C by reducing LDLR protein levels and by stimulating the production of the apoB-containing lipoprotein particles in HepG2 cells. Another drug, cyclophosphamide, did not have any effect on lipid metabolism, indicating drug-specific effects on the HDL and LDL production pathway exist. In conclusion, this PhD thesis has progressed our understanding of Lp(a) metabolism. A potential mechanistic basis for the positive association between Lp(a) and HDL was determined. The intracellular trafficking of Lp(a) in the liver has been shown for the first time to follow a retrograde trafficking and recycling pathway of apo(a). Lp(a) uptake has been shown to be mediated by the plasminogen receptor, PlgRKT. These new findings of the catabolic fate of Lp(a) in the liver may help in tailoring therapeutics to lower plasma Lp(a) levels.
Author: Monika ‡e author Sharma
Publisher:
ISBN:
Category :
Languages : en
Pages : 200
Get Book Here
Book Description
Lipoprotein(a) (Lp(a)) comprises a low density lipoprotein (LDL) particle with one molecule of apolipoprotein B-100 (apoB-100) and one molecule of apolipoprotein(a) [apo(a)], a protein evolutionary derived from plasminogen. The apo(a) protein consists of two plasminogen kringle domains, kringle IV (KIV) and kringle V (KV). KIV is further divided into 10 subclasses, KIV1-10. Repetition of the KIV2 domain is responsible for the size heterogeneity of apo(a) isoforms. The size of apo(a) isoforms is inversely correlated with plasma Lp(a) levels and elevated levels of Lp(a) (>50 mg/dL) are directly associated with cardiovascular disease risk. Plasma Lp(a) levels and cardiovascular disease risk share a “J” shape relationship where lower plasma Lp(a) levels (50 mg/dL) reduces cardiovascular disease risk compared to those with no Lp(a). However, a proportional increase in cardiovascular disease risk is observed with increasing plasma Lp(a) levels (50 mg/dL). The beneficial effects of having low Lp(a) concentrations occur through an unknown mechanism. A significant positive correlation between Lp(a) and high density lipoprotein cholesterol (HDL-C) is observed in African-American populations and in the multi-ethnic Dallas heart study population, indicative of a biological connection between Lp(a) and HDL-C. Previous studies by our group and by others have also suggested that there is a positive connection between Lp(a) and HDL-C where elevated HDL-C levels were observed in Lp(a) transgenic mice. The first aim of this thesis was to investigate the mechanism responsible for the biological connection between Lp(a) and HDL-C. Plasma HDL-C levels are regulated by the expression of several genes in the liver. The HDL biogenesis pathway is primarily regulated by the ATP-binding cassette A1 (ABCA1), a cholesterol transporter. In this study, the effects of Lp(a) on the HDL biogenesis pathway in a hepatic cellular model (HepG2 cells) were investigated. Interestingly, Lp(a) upregulated ABCA1-mediated cholesterol efflux via the peroxisomal proliferator activated receptor and liver X receptor transcription factors. Further investigations revealed that it was the oxidised phospholipid content of Lp(a) that induced ABCA1 expression. Oxidised phospholipids from Lp(a) were delivered via the scavenger receptor-B1 (SR-B1) to stimulate an ABCA1 response in HepG2 cells. An interesting observation from these results was the internalisation of apo(a), independent of the SR-B1-mediated Lp(a) lipid internalisation. Multiple studies have implicated several receptors in Lp(a) uptake, however the precise receptor and mechanism responsible for Lp(a) clearance from plasma remains unknown. The second aim of this thesis was to characterise the uptake and intracellular trafficking of Lp(a) in HepG2 cells. This study has determined that the endocytosed Lp(a) follows an early endosome to trans-Golgi/recycling endosome trafficking route. This retrograde trafficking of Lp(a) recycles apo(a) into the media where it appears to re-assemble Lp(a). Interestingly, Lp(a) uptake was dependent on L-type calcium channels, suggesting calcium-dependent endocytosis in HepG2 cells. Notably, Lp(a) uptake was independent of proposed Lp(a) receptors, the asialoglycoprotein receptor and the LDL receptor. A preliminary investigation has revealed that the plasminogen receptor, PlgRKT might be responsible for Lp(a) internalisation. After establishing the methods to investigate the HDL synthesis pathway, the effects of chemotherapy drugs on lipid metabolism targets were investigated. This work was motivated by the findings of a colleague of my supervisor who had observed a decrease in HDL-C levels in breast cancer patients undergoing chemotherapy. This lead to the third aim: to investigate the effects of chemotherapy drugs (doxorubicin, cyclophosphamide and paclitaxel) on the HDL biogenesis pathway. Surprisingly, doxorubicin, a common chemotherapy agent, lowered HDL-C in HepG2 cells by decreasing ABCA1-mediated cholesterol efflux. Additionally, paclitaxel (another common chemotherapy agent) increased LDL-C by reducing LDLR protein levels and by stimulating the production of the apoB-containing lipoprotein particles in HepG2 cells. Another drug, cyclophosphamide, did not have any effect on lipid metabolism, indicating drug-specific effects on the HDL and LDL production pathway exist. In conclusion, this PhD thesis has progressed our understanding of Lp(a) metabolism. A potential mechanistic basis for the positive association between Lp(a) and HDL was determined. The intracellular trafficking of Lp(a) in the liver has been shown for the first time to follow a retrograde trafficking and recycling pathway of apo(a). Lp(a) uptake has been shown to be mediated by the plasminogen receptor, PlgRKT. These new findings of the catabolic fate of Lp(a) in the liver may help in tailoring therapeutics to lower plasma Lp(a) levels.
Author: H. Greten
Publisher: Springer Science & Business Media
ISBN: 3642709567
Category : Medical
Languages : en
Pages : 232
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Book Description
Cell surface receptors are multifunctional proteins with binding sites towards the external environment and effector sites which mediate intracellular events. The purpose of this symposium was to bring together investigators who have a com mon interest in those receptors which are located in the liver, and who have studied endocytic mechanisms for various macromolecules like insulin, lipoproteins, epi dermal growth factor and others. Experiments in this particular field of research date back to the early 60-ies but have only recently led to new and important in sight in the molecular basis of receptor mediated uptake in the liver. The structural features which control these mechanisms are currently under intense investigation in many laboratories. Though this symposium largely emphasizes lipoprotein up take and catabolism by the liver, it was the particular intention of the organizers to discuss methodology and results with investigators who are also interested in he patic uptake of macromolecules. This might then eventually lead to new and com mon concepts for both receptor-ligand interaction and internalization processes in the liver. Biochemists, pathologists and gastroenterologists met for two and a half days and discussed their latest data in this so rapidly developing field of basic rese arch. This conference is part of a series on current topics in gastroenterology and hepatology arranged regularly by the Departments of Medicine and Surgery at the University Hospital Eppendorf. If is our hope, that such exchange of information between the different disciplines in medicine will continue. i. k.
Author: Irwin M. Arias
Publisher: John Wiley & Sons
ISBN: 1119436826
Category : Medical
Languages : en
Pages : 1156
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Book Description
Bridging the gap between basic scientific advances and the understanding of liver disease — the extensively revised new edition of the premier text in the field. The latest edition of The Liver: Biology and Pathobiology remains a definitive volume in the field of hepatology, relating advances in biomedical sciences and engineering to understanding of liver structure, function, and disease pathology and treatment. Contributions from leading researchers examine the cell biology of the liver, the pathobiology of liver disease, the liver’s growth, regeneration, metabolic functions, and more. Now in its sixth edition, this classic text has been exhaustively revised to reflect new discoveries in biology and their influence on diagnosing, managing, and preventing liver disease. Seventy new chapters — including substantial original sections on liver cancer and groundbreaking advances that will have significant impact on hepatology — provide comprehensive, fully up-to-date coverage of both the current state and future direction of hepatology. Topics include liver RNA structure and function, gene editing, single-cell and single-molecule genomic analyses, the molecular biology of hepatitis, drug interactions and engineered drug design, and liver disease mechanisms and therapies. Edited by globally-recognized experts in the field, this authoritative volume: Relates molecular physiology to understanding disease pathology and treatment Links the science and pathology of the liver to practical clinical applications Features 16 new “Horizons” chapters that explore new and emerging science and technology Includes plentiful full-color illustrations and figures The Liver: Biology and Pathobiology, Sixth Edition is an indispensable resource for practicing and trainee hepatologists, gastroenterologists, hepatobiliary and liver transplant surgeons, and researchers and scientists in areas including hepatology, cell and molecular biology, virology, and drug metabolism.
Author: Armin Steinmetz
Publisher: Springer Science & Business Media
ISBN: 3642848559
Category : Science
Languages : en
Pages : 311
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Book Description
An intimate relation between hormones and lipoprotein metabolism has been known for a long time especially from hormone-deficiency or -overproduction syndromes. The mechanisms through which hormones influence lipid metabolism have become a field of major interest in sci ence. The more we learn about cellular hormonal actions the better we understand regulatory processes and phenomena occuring in patients. The present book summarizes data discussed at an International Meet ing at Marburg, Germany, on "Hormones in Lipoprotein Metabolism". It was an attempt to pull together knowledge in basic science from the mode of action of hormones all the way to clinical appearance of hor monal disorders involving lipoprotein metabolism. Thus data on molec ular biology, on hormonal regulation of apolipoprotein synthesis, on lipoprotein receptors and enzyme induction are discussed together with the large field of oral contraceptive use, postmenopausal estrogen sub stitution, lipid disorders in diabetes mellitus, in thyroid dysfunction, in adrenal insufficiency and in glucocorticoid application. We are aware of the fact that such an overview cannot be complete but should serve as a collection of data and ideas for those interested in hormonal regulation of lipid metabolism. We thank all authors for taking an extra effort in writing up their presentations and thus making this edition possible. We also thank Bristol-Myers-Squibb for generous support of the meeting and of the final publication. Marburg, Germany ARMIN STEINMETZ JURGEN SCHNEIDER HANS KAFFARNIK Contents Molecular Biology Chairmen: D. J. Rader, A.
Author: H. Greten
Publisher: Springer
ISBN:
Category : Medical
Languages : en
Pages : 190
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Book Description
Symposium on Lipoprotein Metabolism, held in Heidelberg, September 10-13, 1975
Author: N Myant
Publisher: Elsevier
ISBN: 0323148875
Category : Science
Languages : en
Pages : 480
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Book Description
Cholesterol Metabolism, LDL, and the LDL Receptor focuses on the cholesterol biochemistry and lipoprotein metabolism. This book is organized into 10 chapters that describe the coordinated actions of three regulated processes, namely, the intracellular synthesis of cholesterol, its esterification by ACAT, and the receptor-mediated uptake of low-density lipoprotein (LDL), for optimal level of free cholesterol. The first five chapters explore the various aspects of cholesterol biology, including discussions on the interaction of ligands with their cell-surface receptors; the role of coated pits in the endocytosis of receptor-bound ligands; and the recycling of receptors through the interior of the cell. These chapters also examine the regulation of gene expression encoding inducible proteins and the use of natural and synthetic mutations in studies of the functions of the separate domains of a multifunctional protein. A chapter describes the cloning of the apoB gene, the receptor-binding domain of apoB-100, and the unusual mode of derivation of apoB-48. Considerable chapters are devoted to LDL receptor and its pathway. The concluding chapter deals with the clinical consequences of genetic dysfunction of the LDL receptor, with particular emphasis on the diagnostic and treatment approaches of familial hypercholesterolemia that are based wholly or in part on knowledge of the LDL receptor or its gene. This book is an indispensable guide for biologists, physiologists, and clinicians who are interested in the epidemiological field of cholesterol and heart attacks.
Author: T. Kita
Publisher: Springer Science & Business Media
ISBN: 4431684247
Category : Medical
Languages : en
Pages : 530
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Book Description
Atherosclerosis leading to coronary heart disease and to cerebrovascular disorders is the number one cause of death in industrialized societies. For the last two decades, great ad vances have been made in understanding the pathogenesis of those disorders. Recent studies have revealed that the earliest event in atherogenesis is the adhesion of circulating leukocytes to the vascular endothelial cells and their migration into the subendothelial space. These cells are known to playa central role in the formation of a fatty streak consist ing of lipid-laden foam cells. As pathological events continue, the lesion is converted to a more fibrous lesion associated with vascular smooth muscle cells. To solve the enigma of this complicated process, intensive studies in molecular biology have disclosed the genes involved in those events. Some of the genes have been verified by creation of novel animal models, which have led to novel therapeutic strategies for subjects with atherosclerosis. This volume contains papers presented at the International Symposium on Lipoprotein Metabolism and Atherogenesis held in Kyoto December 5-8, 1998, supported in part by the Japan Intractable Diseases Research Foundation. The following three topics were the focus of the three-day program: I) The molecular approach to studying risk factors and prevention 2) The creation of novel animal models 3) Lipoprotein disorder as a cause of activation of vascular endothelial cells Thirty distinguished researchers from the United States, the United Kingdom, Austria, Finland, Australia, and Japan were invited.
Author: Jean-Pierre Montmayeur
Publisher: CRC Press
ISBN: 1420067761
Category : Medical
Languages : en
Pages : 646
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Book Description
Presents the State-of-the-Art in Fat Taste TransductionA bite of cheese, a few potato chips, a delectable piece of bacon - a small taste of high-fat foods often draws you back for more. But why are fatty foods so appealing? Why do we crave them? Fat Detection: Taste, Texture, and Post Ingestive Effects covers the many factors responsible for the se
Author: Anatol Kontush
Publisher: John Wiley & Sons
ISBN: 1118158660
Category : Science
Languages : en
Pages : 786
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Book Description
A complete guide to the role of high-density lipoproteins (HDL) in new and emerging therapies With high-density lipoproteins (HDL) playing an increasing role in cardiovascular disease prevention, there is a growing need for an in-depth look at HDL and its clinical value. This book summarizes the current state of knowledge in the field, providing for the first time a comprehensive, systematic, stylistically coherent, and up-to-date review of the composition, structure, heterogeneity, metabolism, epidemiology, genetics, and function of HDL. Divided into three main parts, High-Density Lipoproteins first examines normal HDL particles, then describes defective HDL, and finally addresses the therapeutic normalization of subnormal levels and defective biological activities of this lipoprotein class. The book highlights the functional properties of HDL, which are relevant to the pathophysiology of atherosclerosis and thrombosis, and discusses the compositional and metabolic heterogeneity of HDL particles. Readers will come away with a clear understanding of the role of HDL in biological processes, the potential value of functional HDL as a therapeutic target, and how current and emerging therapies are poised to influence the treatment of heart disease in the future.
Author: Rodolfo Paoletti
Publisher: Springer Science & Business Media
ISBN: 3642717020
Category : Science
Languages : en
Pages : 467
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Book Description
The recent symposium and the appearance of this new book on Drugs Affecting Lipid Metabolism take place at a very unusual time for the development of this area. After the publication and wide acceptance of the results of the cholestyramine study by the Lipid Clinics in the USA, showing for the first time a direct association between drug induced reduction of plasma levels of total and LDL cholesterol and coronary heart disease in a high risk population, an unparalleled interest in drugs and other procedures able to control plasma cholesterol levels has been activated. Two other significant events occurred during 1986 and 1987: the availability of compact instruments for the immediate determination of total cholesterol in plasma or total blood and the developments of new agents such as the inhibitors of HMG-CoA (hydroxymethyl glutaryl CoA) reductase and ACAT inhibitors, with potentially great effect on plasma lipid levels after oral administration. These new advances, together with the combined efforts of cell biologists and lipoprotein chemists, have set the pace for an exciting period of research and clinical applications of diets and drugs af fecting lipids. This volume, which includes the work of many of the leading world laboratories, represents an authoritative and up-to-date ap praisal of the status of the art and a stimulus to future research at laboratory and clinical level in an area of opportunity for clinical and preventive medicine.
