title: Complete deficiency of the low-density lipoprotein receptor is associated with increased apolipoprotein B-100 production.
abstract: OBJECTIVE
  We addressed the role of the low-density lipoprotein (LDL) receptor in determining clearance rates and production rate (PR) of apolipoprotein B (apoB) in humans.
  
  
  RESULTS
  Kinetic studies using endogenous labeling of apoB with deuterated leucine were performed in 7 genetically defined patients with homozygous familial hypercholesterolemia (FH) and compared with 4 controls. The fractional catabolic rates (FCR) and PRs for apoB were determined by multicompartmental modeling. The FCRs of very-low-density lipoprotein 1 (VLDL1), VLDL2, intermediate-density lipoprotein (IDL), and LDL apoB were lower in FH than in controls, with the LDL apoB FCR being significantly lower (0.148+/-0.049 versus 0.499+/-0.099 pools x d(-1); P=0.008). Whereas receptor-defective FH patients had a total apoB PR similar to controls, receptor-null FH patients had a significantly greater total apoB PR than controls (35.97+/-10.51 versus 21.32+/-4.21 mg x kg(-1) x d(-1), respectively; P=0.02).
  
  
  CONCLUSIONS
  This first study of apoB metabolism in homozygous FH using endogenous labeling with stable isotopes demonstrates that the LDL receptor contributes significantly to the clearance of LDL from plasma but plays a lesser role in the clearance of larger apoB-containing lipoproteins. Furthermore, these data also indicate that absence of a LDL receptor in humans substantially influences the apoB PR in vivo.
authors.affiliation: Department of Medicine, University of Pennsylvania, 644 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104, USA. jsmillar@mail.med.upenn.edu
authors.forename: John S
authors.initials: JS
authors.lastname: Millar
authors.forename: Cyrille
authors.initials: C
authors.lastname: Maugeais
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikewaki
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Kolansky
authors.forename: P Hugh R
authors.initials: PH
authors.lastname: Barrett
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Budreck
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Boston
authors.forename: Norio
authors.initials: N
authors.lastname: Tada
authors.forename: Seibu
authors.initials: S
authors.lastname: Mochizuki
authors.forename: Joep C
authors.initials: JC
authors.lastname: Defesche
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
mesh_terms: D000293:Adolescent; D000328:Adult; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000096:biosynthesis / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D005260:Female; D006720:Homozygote; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics* / Q000378:metabolism*; D007930:Leucine / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D014316:Tritium
chemical_list: D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D011973:Receptors, LDL; D014316:Tritium; D007930:Leucine