HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: M500487-JLR200v1 47/3/622    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, C. Y. Articles by Marcil, M. Search for Related Content PubMed PubMed Citation Articles by Lee, C. Y. Articles by Marcil, M. Social Bookmarking                      What's this?

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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. E. Saslowsky, N. Tanaka, K. P. Reddy, and W. I. Lencer Ceramide activates JNK to inhibit a cAMP-gated K+ conductance and Cl- secretion in intestinal epithelia FASEB J, January 1, 2009; 23(1): 259 - 270. [Abstract] [Full Text] [PDF]