TY - JOUR
T1 - Complete Deficiency of the Low-Density Lipoprotein Receptor Is Associated With Increased Apolipoprotein B-100 Production
AU - Millar, J.S.
AU - Maugeais, C.
AU - Ikewaki, K.
AU - Kolansky, D.M.
AU - Barrett, Hugh
AU - Budreck, E.C.
AU - Boston, R.C.
AU - Tada, N.
AU - Mochizuki, S.
AU - Defesche, J.C.
AU - Wilson, J.M.
AU - Rader, D.J.
PY - 2005
Y1 - 2005
N2 - 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.Methods and 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 . 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 . kg(-1) . 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.
AB - 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.Methods and 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 . 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 . kg(-1) . 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.
U2 - 10.1161/01.ATV.0000155323.18856.a2
DO - 10.1161/01.ATV.0000155323.18856.a2
M3 - Article
C2 - 15637307
SN - 1079-5642
VL - 25
SP - 560
EP - 565
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 3
ER -