Accumulation of "small dense" low density lipoproteins (LDL) in a homozygous patients with familial defective apolipoprotein B-100 results from heterogenous interaction of LDL subfractions with the LDL receptor.
The interaction of LDL and LDL subfractions from a patient homozygous for familial defective apoB-100 (FDB) has been studied. His LDL cholesterol ranged from 2.65 to 3.34 g/liter. In cultured fibroblasts, binding, internalization, and degradation of the patient's LDL was diminished, but not completely abolished. The patient's apolipoprotein E concentration was low, and the amount of apolipoprotein E associated with LDL was not elevated over normal. LDL were separated into six subfractions: LDL-1 (1.019-1.031 kg/liter), LDL-2 (1.031-1.034 kg/liter), LDL-3 (1.034-1.037 kg/liter), LDL-4 (1.037-1.040 kg/liter), LDL-5 (1.040-1.044 kg/liter), and LDL-6 (> 1.044 kg/liter). LDL-5 and LDL-6 selectively accumulated in the patient's plasma. Concentrations of LDL-1 to 3 were normal. The LDL receptor-mediated uptake of LDL-1 and LDL-2 could not be distinguished from normal LDL. LDL-3 and LDL-4 displayed reduced uptake; LDL-5 and LDL-6 were completely defective in binding. When apolipoprotein E-containing particles were removed by immunoabsorption before preparing subfractions, LDL-3 and LDL-4, but not LDL-1 and LDL-2, retained some receptor binding activity. We conclude that in FDB, LDL-1 and LDL-2 contain sufficient apolipoprotein E to warrant normal cellular uptake. In LDL-3 and LDL-4, the defective apoB-100 itself displays some receptor binding; LDL-5 and LDL-6 are inable to interact with LDL receptors and accumulate in plasma.
März
W
W
Gustav Embden-Center of Biological Chemistry, Johann Wolfgang Goethe-University, Frankfurt, Germany.
Baumstark
M W
MW
Scharnagl
H
H
Ruzicka
V
V
Buxbaum
S
S
Herwig
J
J
Pohl
T
T
Russ
A
A
Schaaf
L
L
Berg
A
A
D000293:Adolescent; D000328:Adult; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002784:Cholesterol / Q000097:blood; D017931:DNA Primers; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006580:Genetic Carrier Screening; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood; D008077:Lipoproteins, LDL / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017035:Pravastatin / Q000627:therapeutic use; D011973:Receptors, LDL / Q000378:metabolism*; D012867:Skin / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D017931:DNA Primers; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; D017035:Pravastatin