Benn, Marianne1; Nordestgaard, Børge G3; Jensen, Jan Skov4; Nilausen, Karin Skov5; Meinertz, Hans6; Tybjaerg-Hansen, Anne1
1 Klinisk Biokemisk Afdeling, Diagnostisk Center, Rigshospitalet, The Capital Region of Denmark2 Copenhagen City Heart Study, Bispebjerg and Frederiksberg Hospital, The Capital Region of Denmark3 Clinical Biochemistry, Herlev and Gentofte Hospital, The Capital Region of Denmark4 Cardiology, Herlev and Gentofte Hospital, The Capital Region of Denmark5 University of Copenhagen6 unknown
Mutations in apolipoprotein B (APOB) may reduce binding of low density lipoprotein (LDL) to the LDL receptor and cause hypercholesterolemia. We showed that heterozygotes for a new mutation in APOB have hypobetalipoproteinemia, despite a reduced binding of LDL to the LDL receptor. APOB R3480P heterozygotes were identified among 9,255 individuals from the general population and had reduced levels of apoB-containing lipoproteins. Most surprisingly, R3480P LDL bound with lower affinity to the LDL receptor than non-carrier LDL in vitro, and these results were confirmed by turnover studies of LDL in vivo. In very low density lipoprotein (VLDL) turnover studies, the amount of VLDL converted to LDL in R3480P heterozygotes was substantially reduced, suggesting that this was the explanation for the hypobetalipoproteinemia observed in these individuals. Our findings emphasized the importance of combining in vitro studies with both human in vivo and population-based studies, as in vitro studies often have focused on very limited aspects of complex mechanisms taken out of their natural context.
Journal of Biological Chemistry, 2005, Vol 280, Issue 22, p. 21052-60