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Journal of Lipid Research, Vol. 47, 622-632, March 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Increased sphingomyelin content impairs HDL biogenesis and maturation in human Niemann-Pick disease type B

Ching Yin Lee^*, Alain Lesimple, Maxime Denis^*, Jérôme Vincent^*, Åsmund Larsen, Orval Mamer, Larbi Krimbou^*, Jacques Genest^* and Michel Marcil^1,*

^* Cardiovascular Genetics Laboratory, Department of Medicine, Division of Cardiology, McGill University Health Centre/Royal Victoria Hospital, Montréal, Québec, Canada
Mass Spectrometry Unit, McGill University, Montréal, Québec, Canada
Department of Chemistry, University of Oslo, Oslo, Norway

Published, JLR Papers in Press, November 30, 2005.

¹ To whom correspondence should be addressed. e-mail: michel.marcil{at}mcgill.ca

We previously reported that human Niemann-Pick Disease type B (NPD-B) is associated with low HDL. In this study, we investigated the pathophysiology of this HDL deficiency by examining both HDL samples from NPD-B patients and nascent high density lipoprotein (LpA-I) generated by incubation of lipid-free apolipoprotein A-I (apoA-I) with NPD-B fibroblasts. Interestingly, both LpA-I and HDL isolated from patient plasma had a significant increase in sphingomyelin (SM) mass (50–100%). Analysis of LCAT kinetics parameters (V_max and K_m) revealed that either LpA-I or plasma HDL from NPD-B, as well as reconstituted HDL enriched with SM, exhibited severely decreased LCAT-mediated cholesterol esterification. Importantly, we documented that SM enrichment of NPD-B LpA-I was not attributable to increased cellular mass transfer of SM or unesterified cholesterol to lipid-free apoA-I. Finally, we obtained evidence that the conditioned medium from HUVEC, THP-1, and normal fibroblasts, but not NPD-B fibroblasts, contained active secretory sphingomyelinase (S-SMase) that mediated the hydrolysis of [³H]SM-labeled LpA-I and HDL₃. Furthermore, expression of mutant SMase (R608) in CHO cells revealed that R608 was synthesized normally but had defective secretion and activity. Our data suggest that defective S-SMase in NPD leads to SM enrichment of HDL that impairs LCAT-mediated nascent HDL maturation and contributes to HDL deficiency. Thus, S-SMase and LCAT may act in concert and play a crucial role in the biogenesis and maturation of nascent HDL particles.

Supplementary key words high density lipoprotein • nascent LpA-I • phospholipids • sphingomyelin phosphodiesterase-1 gene • sphingomyelinase

Abbreviations: apoA-I, apolipoprotein A-I; CE, cholesteryl ester; ESI-MS, electrospray ionization-mass spectrometry; FC, free cholesterol; HDL-C, high density lipoprotein-cholesterol; LpA-I, nascent apoA-I-containing particle; NPD-A/B, Niemann-Pick disease type A and B; PC, phosphatidylcholine; PL, phospholipid; rLpA-I, reconstituted apolipoprotein A-I-containing proteoliposomes; SM, sphingomyelin; SMase, sphingomyelinase; SMPD-1, sphingomyelin phosphodiesterase-1 gene; S-SMase, secretory sphingomyelinase; SR-BI, scavenger receptor class B type I; TD, Tangier disease; 2D-PAGGE, two-dimensional polyacrylamide nondenaturing gradient gel electrophoresis; 22OH/9CRA, 2.5 µg/ml 22(R)-hydroxycholesterol and 5 µM 9-cis-retinoic acid

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