Oxidation of apolipoprotein B-100 in circulating LDL is related to LDL residence time. In vivo insights from stable-isotope studies.
5-Hydroxy-2-aminovaleric acid (HAVA) has been suggested to be a specific marker of oxidation of apolipoprotein (apo) B-100 proline (Pro) and arginine (Arg) side-chain residues in low density lipoprotein (LDL) in vitro. Here we describe the application of sensitive mass spectrometric techniques to the characterization of Pro/Arg-modified apoB-100 in LDL(1) (S(f) 7 to 12) and LDL(2) (S(f) 0 to 7) in vivo. We studied 7 subjects with familial defective apoB-100 (FDB) and 8 normolipidemic controls. In FDB subjects, the presence of a mutant apoB-100 (FDB(3500Q)) in LDL markedly reduced its affinity for the LDL receptor, leading to increased residence times (RTs) of LDL(1) (65+/-21 versus 32+/-12 hours, P<0.005) and LDL(2) (230+/-40 versus 53+/-7 hours, P:<0.001) when compared with controls, as determined by stable-isotope turnover studies. LDL(1) HAVA content was not different between the groups (FDB, 0.004+/-0. 001 mol/mol apoB-100 versus controls, 0.003+/-0.001 mol/mol apoB-100, P=0.200). LDL(2) HAVA content was higher in FDB subjects (0. 374+/-0.088 versus 0.013+/-0.002 mol/mol apoB-100, P<0.001). In both groups, LDL(2) HAVA was positively associated with LDL(2) RT (FDB, r=0.893, P:=0.003; controls, r=0.976, P=0.000) and negatively correlated with LDL(2) alpha-tocopherol content (FDB, r=-0.929, P=0. 003; controls, r=-0.903, P=0.002). No significant correlations could be found between LDL(1) HAVA, LDL(1) RT, and alpha-tocopherol, respectively. The low LDL(1) HAVA content observed in both FDB and control groups was thought to be due to the relatively lower RT as well as the higher alpha-tocopherol content of these lipoproteins. In contrast, LDL(2) seemed to be strongly prone to direct oxidation of apoB-100 in vivo. The longer these particles linger in the circulation, the more apoB-100 Pro/Arg residues become modified.
Pietzsch
J
J
Institute and Polyclinic of Clinical Metabolic Research, Technical University Dresden, Dresden, Germany. julius@rcs.urz.tu-dresden.de
Lattke
P
P
Julius
U
U
D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000032:analysis; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000097:blood* / Q000737:chemistry / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000097:blood* / Q000235:genetics; D008077:Lipoproteins, LDL / Q000097:blood* / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010084:Oxidation-Reduction; D011973:Receptors, LDL / Q000378:metabolism; D013997:Time Factors; D014810:Vitamin E / Q000032:analysis
D000596:Amino Acids; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D014810:Vitamin E; C004387:2-amino-5-hydroxyvaleric acid; D002784:Cholesterol