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ePaper created 2014-09-15, 12:31:02 | version 1.32.01
ultrastructural studies. He demonstrated the binding of LDL by cultured fibroblasts using an immunoperoxidase technique. On the ultrastructural level, he was able to show that LDL is bound and internalized by cultured fibroblasts at specific areas of the cell membrane, the so-called coated pits.[4] LDL binding sites were absent in cells derived from a patient who was homozygous for familial hypercholesterolemia. This finding demonstrates the deficient binding of LDL to its receptors in patients with familial hypercholesterolemia, which is caused by mutations in the LDL-receptor gene. The investigations were extended to cultured monocyte-derived macrophages. By using immunofluo- rescence microscopy and electron microscopy Jan Gerrit van der Schroeff showed that monocyte- derived macrophages exhibited LDL binding in a similar way as fibroblasts.[5] With these techniques, no binding sites could be found for acetylated LDL, which is a modified form of LDL that induces cholesterylester accumulation within the cells. Mieke Mommaas-Kienhuis demonstrated, however, that colloidal gold conjugates with LDL and acetylated LDL were internalized by the coated pit/coated vesicle system in monocyte-derived macrophages.[6] She also studied the binding and uptake of LDL and acetylated LDL in other cell types, such as endothelial cells, liver cells and keratinocytes. Further studies on intracellular cholesterylester accumulation in cultured monocyte-derived macrophages revealed that the process of foam cell formation could be suppressed by a HMGCoA reductase inhibitor and by lipoxygenase inhibitors.[7] The results of these studies have contributed significantly to the understanding of atherosclerosis and cardiovascular disease, but at the same time shifted too far away from everyday dermatology. For that reason this successful line of research was discontinued in the early 80s. References 1. Polano MK, Baes H, Hulsmans HAM, et al. Xanthomata in primary hyperlipoproteinaemia: a classification based on the lipoprotein pattern of the blood. Arch Dermatol 1969; 100: 387-400. 2. Hessel LW, Vermeer BJ, Polano MK, et al. Primary hyperlipoproteinemia in xanthomatosis. Clin Chim Acta 1976; 69: 405-16. 3. Vermeer BJ, van Gent CM, Goslings B, Polano MK. Xanthomatosis and other clinical findings in patients with elevated levels of very low density lipoproteins. Br J Dermatol 1979; 100: 657-66. 4. Vermeer BJ, Koster JF, Emeis JJ, et al. Binding of unmodified low-density lipoproteins to human fibroblasts. An investigation by immunoelectron microscopy. Biochim Biophys Acta 1979; 553: 169-74. 5. Schroeff JG van der, Havekes L, Emeis JJ, et al. Morphological studies on the binding of low-density lipoproteins and acetylated low-density lipoproteins to the plasma membrane of cultured monocytes. Exp Cell Res 1983; 145: 95-103. 6. Mommaas-Kienhuis AM, van der Schroeff JG, Wijsman MC, et al. Conjugates of colloidal gold with native and acetylated low density lipoproteins for ultrastructural investigations on receptor-mediated endocytosis by cultured human monocyte-derived macrophages. Histochemistry 1985; 83: 29-35. 7. Schroeff JG van der, Havekes L, Weerheim AM, et al. Suppression of cholesteryl ester accumulation in cultured human monocyte-derived macrophages by lipoxygenase inhibitors. Biochem Biophys Res Commun 1985; 127: 366-72. 85 BWEADVSMGFINCORR:Opmaak 1 21-07-2014 17:40 Pagina 85