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

Abstract
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 ( approximately 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 [(3)H]SM-labeled LpA-I and HDL(3). Furthermore, expression of mutant SMase (DeltaR608) in CHO cells revealed that DeltaR608 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.
AuthorsChing Yin Lee, Alain Lesimple, Maxime Denis, Jérôme Vincent, Asmund Larsen, Orval Mamer, Larbi Krimbou, Jacques Genest, Michel Marcil
JournalJournal of lipid research (J Lipid Res) Vol. 47 Issue 3 Pg. 622-32 (Mar 2006) ISSN: 0022-2275 [Print] United States
PMID16319418 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Lipoproteins, HDL
  • Phospholipids
  • Sphingomyelins
  • Cholesterol
  • Sphingomyelin Phosphodiesterase
Topics
  • Adult
  • Animals
  • CHO Cells
  • Cells, Cultured
  • Cholesterol (metabolism)
  • Cricetinae
  • Female
  • Fibroblasts (metabolism)
  • Humans
  • Lipoproteins, HDL (metabolism)
  • Male
  • Middle Aged
  • Niemann-Pick Diseases (blood, metabolism)
  • Phospholipids (metabolism)
  • Sphingomyelin Phosphodiesterase (metabolism)
  • Sphingomyelins (metabolism, pharmacology)
  • Transfection

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