Submitted on November 7, 2005
Revised on November 29, 2005
Accepted on November 30, 2005
Increased sphingomyelin content impairs HDL biogenesis and maturation in human Niemann-Pick disease type B
Ching Yin Lee, Alain Lesimple, Maxime Denis, Jérome Vincent, Asmund Larsen, Orval Mamer, Larbi Krimbou, Jacques Genest, and Michel Marcil
Dept. of Cardiology, McGill University Health Center, Montreal, QC H3A 1A1
Corresponding Author: michel.marcil{at}mcgill.ca
We have previously reported that human Niemann-Pick Disease type B (NPD-B) is associated with low HDL. In the present study, we investigated the pathophysiology of this HDL deficiency by examining both HDL samples from NPD-B patients and nascent HDL (LpA-I) generated by incubation of lipid-free apoA-I with NPD-B fibroblasts. Interestingly, both nascent LpA-I and HDL isolated from the patients’ plasma had a significant increase in SM mass (~ 50% to 100%). Analysis of LCAT kinetics parameters (Vmax and Km) revealed that either nascent 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 nascent 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 nascent LpA-I and HDL3. Furthermore, expression of mutant SMase (DR608) in CHO cells revealed that DR608 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 impaired 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.
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