Untersuchungen zum ABCA1-/ABCG1-vermittelten Cholesterin-Efflux in humanen Kontroll- und Tangierfibroblasten
The formation of high density lipoproteins (HDL) and the reverse cholesterol transport are of immense clinical importance. A low HDL plasma concentration promotes atherogenesis and therefore is one of the most important cardiovascular risk factors. The ABC transporters A1 and G1 (ABCA1 and ABCG1), which mediate the cholesterol efflux from the cell to the HDL, play an essential role in HDL formation. Therefore, ABCA1 and ABCG1 expression, function and regulation are essential for understanding
... for understanding the various forms of HDL deficits and their possible atherogenicity. In the present thesis the expression of ABCA1 and ABCG1 in human control fibroblasts and Tangier fibroblasts was compared. The mRNA expression was analyzed through real-time PCR, the protein expression via Western blotting. Tangier disease is characterized by various mutations in the ABCA1 gene. In this thesis Tangier disease served as a model disease for a severe form of HDL deficiency. In Tangier fibroblasts with low residual ABCA1 activity (point mutation in exon 19, clinically mild phenotype with low arteriosclerosis) an increased ABCA1 and ABCG1 expression was found. In contrast, Tangier fibroblasts with a functional ABCA1 knockout (nonsense mutation in Exon 13, clinically severe phenotype with severe arteriosclerosis) showed a reduced expression of both transporters. An increased ABCA1 and ABCG1 expression in Tangier fibroblasts seems to at least partially compensate for decreased ABCA1 activity and to explain the milder phenotype (low arteriosclerosis) in affected patients. In addition, the results show a regulatory relationship in that both transporters in Tangier fibroblasts are regulated up or down at the same time. The parallel occurrence of increased or decreased levels of both transporters points to a coordinated regulation of the expression of the two proteins.