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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2410.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Enhanced Conversion of Triglyceride-Rich Lipoproteins and Increased Low-Density Lipoprotein Removal in LPLS447X Carriers

Melchior C. Nierman; Berthil H.C.M.T. Prinsen; Jaap Rip; Robert Jan Veldman; Jan Albert Kuivenhoven; John J.P. Kastelein; Monique G.M. de Sain-van der Velden; Erik S.G. Stroes

From the Departments of Vascular Medicine (M.C.N., J.J.P.K., E.S.G.S.) and Experimental Vascular Medicine (J.R., R.J.V., J.A.K.), Academic Medical Center, University of Amsterdam, the Netherlands; and the Department of Metabolic and Endocrine Diseases (B.H.C.M.T.P., M.G.M.d.S.-v.d.V.), University Medical Center Utrecht, the Netherlands.

Correspondence to Erik S.G. Stroes, Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, the Netherlands, Meibergdreef 9, 1105 AZ Amsterdam. E-mail e.s.stroes{at}amc.uva.nl

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.

Methods and 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.

We evaluated apoB100 kinetics in homozygous LPLS447X carriers using an L-[1-¹³C]-valine infusion to test the hypothesis of improved apoB100 metabolism in carriers. Enhanced TRL conversion and enhanced LDL removal with increased preheparin LPL concentration in carriers suggest increased enzymatic as well as nonenzymatic consequences of LPL in LPLS447X carriers.

Key Words: lipoprotein lipase • LPLS447X • apolipoproteins • metabolism • apoB100

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