ABSTRACT
The concept that selective transfer of high density lipoprotein (HDL)-derived cholesteryl esters (CE) does not require lipoprotein internalization has been challenged recently by evidence that implicates HDL recycling during the selective uptake process. This has prompted us to examine the role of the low density lipoprotein receptor-related protein (LRP) in selective uptake. LRP is an endocytic receptor for lipoprotein lipase (LpL) and apolipoprotein E (apoE) ligands that are able to mediate selective uptake. We report that molecules that interfere with ligand binding to LRP, such as the receptor-associated protein (RAP), suramin, alpha(2)-macroglobulin, or lactoferrin, inhibit HDL-CE selective uptake by human primary adipocytes and SW872 liposarcoma cells by 35-50%. This partial inhibition of selective uptake from total HDL was not due to preferential inhibition of the HDL(2) or HDL(3) subfractions. Selective uptake by the scavenger receptor BI was not inhibited by RAP, excluding its involvement. Furthermore, in SW872 cells in which LRP was reduced to 14% of control levels by stable antisense expression, selective uptake was attenuated by at least 33%, confirming a role for LRP in this process. RAP, alpha(2)-macroglobulin, lactoferrin, and suramin (individually or in paired combinations) also attenuated selective uptake of HDL-CE by primary human adipocytes by about 40%. On the other hand, human skin fibroblasts express LRP abundantly but lack the capacity for selective uptake, demonstrating that other molecules are required. In SW872 cells, exogenous apoE or LpL can facilitate selective uptake but only the apoE-enhanced uptake can be inhibited by RAP, implicating apoE as a likely co-mediator. We discuss the possible mechanisms by which the endocytic receptor, LRP, can mediate selective uptake.
Subject(s)
Adipocytes/metabolism , Cholesterol Esters/metabolism , LDL-Receptor Related Proteins/metabolism , Lipoproteins, HDL/metabolism , Adipocytes/drug effects , Antineoplastic Agents/pharmacology , Apolipoproteins E/metabolism , Biological Transport , Cells, Cultured , Humans , LDL-Receptor Related Protein-Associated Protein/pharmacology , Lactoferrin/pharmacology , Lipoprotein Lipase/metabolism , Liposarcoma , Macroglobulins/pharmacology , Suramin/pharmacology , Tumor Cells, CulturedABSTRACT
We studied a large consanguineous Anatolian family with children who exhibited hydranencephaly associated with microcephaly. The children were severely affected. This novel genetic disorder is autosomal recessive. We used autozygosity mapping to identify a locus at chromosome 16p13.3-12.1; it has a LOD score of 4.11. The gene locus is within a maximal 11-cM interval between markers D16S497 and D16S672 and within a minimal critical region of 8 cM between markers D16S748 and D16S490.
Subject(s)
Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 16/genetics , Hydranencephaly/genetics , Microcephaly/genetics , Abnormalities, Multiple/physiopathology , Body Height , Body Weight , Child, Preschool , Chromosome Mapping , Consanguinity , Fatal Outcome , Female , Genes, Recessive/genetics , Haplotypes/genetics , Heterozygote , Humans , Hydranencephaly/complications , Hydranencephaly/physiopathology , Infant , Lod Score , Male , Microcephaly/complications , Microcephaly/physiopathology , Odds Ratio , Pedigree , TurkeyABSTRACT
Patterns of dystrophin gene deletions in DMD/BMD patients were compared in four populations: Turks (n = 146 deletions), Europeans (n = 838), North Indians (n = 89), and Indians from all over India (n = 103). Statistical tests revealed that there are differences in the proportions of small deletions. In contrast, the distribution of deletion breakpoints and the frequencies of specific deletions commonly observed in the four populations are not significantly different. The variations strongly suggest that sequence differences exist in the introns, and the differences are in agreement with genetic distances among populations. The similarities suggest that some intronic sequences have been conserved and that those will trigger recurrent deletions, since it is unlikely that gene flow would disperse the deleted chromosomes, which vanish from the gene pool in a few generations.