Enhanced conversion of triglyceride-rich lipoproteins and increased low-density lipoprotein removal in LPLS447X carriers.
OBJECTIVE
Lipoprotein lipase (LPL) exerts 2 principal actions, comprising enzymatic hydrolysis of triglyceride-rich lipoproteins (TRLs) and nonenzymatic ligand capacity for enhancing lipoprotein removal. The common LPLS447X variant has been associated with cardiovascular protection, for which the mechanism is unknown. We therefore evaluated enzymatic and nonenzymatic consequences of this LPL variant on TRL metabolism.


RESULTS
TRL apolipoprotein B100 (apoB100) metabolism was determined in 5 homozygous LPLS447X carriers and 5 controls. Subjects were continuously fed and received infusion of stable isotope l-[1-(13C)]-valine. Results were analyzed by SAAMII modeling. Also, preheparin and postheparin LPL concentration and activity were measured. Compared with controls, carriers presented increased very low-density lipoprotein 1 (VLDL1) to VLDL2 apoB100 flux (P=0.04), increased VLDL2 to intermediate-density lipoprotein (IDL) apoB100 flux (P=0.02), increased IDL to low-density lipoprotein (LDL) apoB100 flux (P=0.049), as well as an increased LDL clearance (P=0.04). Additionally, IDL apoB100 synthesis was attenuated (P=0.05). Preheparin LPL concentration was 4-fold higher compared with controls (P=0.01), and a correlation was observed between preheparin LPL concentration and LDL clearance (r2=0.92; P=0.01).


CONCLUSIONS
Enhanced TRL conversion and enhanced LDL removal combined with increased preheparin LPL concentration suggest increased enzymatic consequences as well as increased nonenzymatic consequences of LPL in LPLS447X carriers, which might both contribute to the cardiovascular benefit of this LPL variant.
Nierman
Melchior C
MC
Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands.
Prinsen
Berthil H C M T
BH
Rip
Jaap
J
Veldman
Robert Jan
RJ
Kuivenhoven
Jan Albert
JA
Kastelein
John J P
JJ
de Sain-van der Velden
Monique G M
MG
Stroes
Erik S G
ES
D000328:Adult; D000925:Anticoagulants; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D002247:Carbon Isotopes; D004041:Dietary Fats / Q000493:pharmacokinetics; D006493:Heparin; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008071:Lipoprotein Lipase / Q000235:genetics* / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D014280:Triglycerides / Q000378:metabolism*; D014633:Valine / Q000493:pharmacokinetics
D000925:Anticoagulants; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D002247:Carbon Isotopes; D004041:Dietary Fats; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D006493:Heparin; D008071:Lipoprotein Lipase; D014633:Valine