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- Boren, Jan, et al.
(författare)
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The molecular mechanism for the genetic disorder familial defective apolipoprotein B100
- 2001
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 276:12, s. 9214-9218
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Tidskriftsartikel (refereegranskat)abstract
- Familial defective apolipoprotein B100 (FDB) is a genetic disorder in which low density lipoproteins (LDL) bind defectively to the LDL receptor, resulting in hypercholesterolemia and premature atherosclerosis. FDB is caused by a mutation (R3500Q) that changes the conformation of apolipoprotein (apo) B100 near the receptor-binding site. We previously showed that arginine, not simply a positive charge, at residue 3500 is essential for normal receptor binding and that the carboxyl terminus of apoB100 is necessary for mutations affecting arginine 3500 to disrupt LDL receptor binding. Thus, normal receptor binding involves an interaction between arginine 3500 and tryptophan 4369 in the carboxyl tail of apoB100. W4369Y LDL and R3500Q LDL isolated from transgenic mice had identically defective LDL binding and a higher affinity for the monoclonal antibody MB47, which has an epitope flanking residue 3500. We conclude that arginine 3500 interacts with tryptophan 4369 and facilitates the conformation of apoB100 required for normal receptor binding of LDL. From our findings, we developed a model that explains how the carboxyl terminus of apoB100 interacts with the backbone of apoB100 that enwraps the LDL particle. Our model also explains how all known ligand-defective mutations in apoB100, including a newly discovered R3480W mutation in apoB100, cause defective receptor binding.
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- Borén, Thomas, 1967-
(författare)
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Meeting-places of Transformation : Urban Identity, Spatial Representations and Local Politics in St Petersburg, Russia
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This study develops a model for understanding spatial change and the construction of space as a meeting-place, and then employs it in order to show an otherwise little-known picture of (sub-)urban Russia and its transformation from Soviet times to today. The model is based on time-geographic ideas of time-space as a limited resource in which forces of various kinds struggle for access and form space in interaction with each other. Drawing on cultural semiotics and the concepts of lifeworld and system, the study highlights the social side of these space-forming forces. Based on a long-term fieldwork (participant observation) in Ligovo/Uritsk, a high-rise residential district developed around 1970 and situated on the outskirts of Sankt-Peterburg (St Petersburg), the empirical material concerns processes of urban identity, spatial representations and local politics. The study explicates three codes used to form the image of the city that all relate to its pre-Revolutionary history, two textual strategies of juxtaposition in creating the genius loci of a place, and a discussion of what I call Soviet "stiff landscape" in relation to Soviet mental and ordinary maps of the urban landscape. Moreover, the study shows that the newly implemented self-governing municipalities have not realised their potential as political actors in forming local space, which raises questions on the democratisation of urban space. Finally, the study argues that the model that guides the research is a tool that facilitates the application of the world-view of time-geography and the epistemology of the landscape of courses in concrete research. The study ends with an attempt to generalise spatial change in four types.
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- Li, Lu, 1964, et al.
(författare)
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The Importance of GLUT3 for De Novo Lipogenesis in Hypoxia-Induced Lipid Loading of Human Macrophages
- 2012
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 7:8
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Tidskriftsartikel (refereegranskat)abstract
- Atherosclerotic lesions are characterized by lipid-loaded macrophages (foam cells) and hypoxic regions. Although it is well established that foam cells are produced by uptake of cholesterol from oxidized LDL, we previously showed that hypoxia also promotes foam cell formation even in the absence of exogenous lipids. The hypoxia-induced lipid accumulation results from increased triglyceride biosynthesis but the exact mechanism is unknown. Our aim was to investigate the importance of glucose in promoting hypoxia-induced de novo lipid synthesis in human macrophages. In the absence of exogenous lipids, extracellular glucose promoted the accumulation of Oil Red O-stained lipid droplets in human monocyte-derived macrophages in a concentration-dependent manner. Lipid droplet accumulation was higher in macrophages exposed to hypoxia at all assessed concentrations of glucose. Importantly, triglyceride synthesis from glucose was increased in hypoxic macrophages. GLUT3 was highly expressed in macrophage-rich and hypoxic regions of human carotid atherosclerotic plaques and in macrophages isolated from these plaques. In human monocyte-derived macrophages, hypoxia increased expression of both GLUT3 mRNA and protein, and knockdown of GLUT3 with siRNA significantly reduced both glucose uptake and lipid droplet accumulation. In conclusion, we have shown that hypoxia-induced increases in glucose uptake through GLUT3 are important for lipid synthesis in macrophages, and may contribute to foam cell formation in hypoxic regions of atherosclerotic lesions.
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