PubMed · 3061155
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B Choluj, T Votruba, L Táborský, E Kormúth. 1988. [Apolipoproteinopathies].. https://pubmed.ncbi.nlm.nih.gov/3061155/
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Lipid-free apolipoprotein (apo) A-I contributes to the reverse transport of cholesterol from the periphery to the liver by solubilizing plasma membrane phospholipid and cholesterol. The features of the apolipoprotein required for this process are not understood and are addressed in the current study. Membrane microsolubilization of human fibroblasts is not specific for apo A-I; unlipidated apos A-II, C, and E incubated with the fibroblast monolayers at a saturating concentration of 50 micrograms/ml are all able to release cholesterol and phospholipid similarly. To determine the properties of the apolipoprotein that drive the process, apo A-I peptides spanning the entire sequence of the protein were utilized; the peptides correspond to the 11- and 22-residue amphipathic alpha-helical segments, as well as adjacent combinations of the helices. Of the 20 helical peptides examined, only peptides representing the N-and C-terminal portions of the protein had the ability to solubilize phospholipid and cholesterol. Cholesterol efflux to the most effective peptides, 44-65 and 209-241, was approximately 50 and 70%, respectively, of that to intact apo A-I. Deletion mutants of apo E and apo A-I were constructed that have reduced lipid binding affinities as compared with the intact molecule. The proteins, apo A-I (Delta222-243), apo A-I (Delta190-243), apo E3 (Delta192-299) and apo E4 (Delta192-299) all exhibited a decreased ability to remove cellular cholesterol and phospholipid. These decreases correlated with the reduced ability of these proteins to penetrate into a phospholipid monomolecular film. Overall, the results indicate that insertion of amphipathic alpha-helices between the plasma membrane phospholipid molecules is a required step in the mechanism of apolipoprotein-mediated cellular lipid efflux. Therefore the lipid binding ability of the apolipoprotein is critical for efficient membrane microsolubilization.
There is accumulating evidence for the importance of small, dense low-density lipoprotein (LDL), the defining feature of the atherogenic lipoprotein phenotype, as a risk factor for coronary heart disease. Although both family studies and twin studies have demonstrated genetic influences on this phenotype, the specific gene(s) involved remain to be identified. The purpose of this study was to determine whether there was evidence for genetic linkage between small, dense LDL (LDL subclass phenotype B), as determined by gradient gel electrophoresis, and selected candidate genes known to be involved in lipid metabolism. The linkage analyses were based on a sample of 19 families, including 142 individual family members, using a lod score linkage analysis approach. Nine candidate genes were examined, including loci for manganese superoxide dismutase (Mn SOD2), apolipoproteins CIII, AII, and apo CII, lipoprotein lipase, hepatic lipase, microsomal triglyceride transport protein, the insulin receptor and the LDL receptor. The analyses did not provide significant evidence for genetic linkage between markers for any of these genes and LDL subclass phenotype B, nor did it confirm previous reports of linkage between the LDL receptor gene and LDL subclass phenotype B. Using three closely linked markers for the Mn SOD2 locus excluded close linkage between this candidate gene region and LDL subclass phenotype B. These findings demonstrate the complexity of genetically mapping risk factor phenotypes, and emphasize the necessity of identifying new genetic loci, other than known candidate genes, involved in susceptibility to atherosclerosis.
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