Ontogenic changes in lung cholesterol metabolism, lipid content, and histology in mice with Niemann–Pick type C disease

Abstract

Niemann-Pick Type C (NPC) disease is caused by a deficiency of either NPC1 or NPC2. Loss of function of either protein results in the progressive accumulation of unesterified cholesterol in every tissue leading to cell death and organ damage. Most literature on NPC disease focuses on neurological and liver manifestations. Pulmonary dysfunction is less well described. The present studies investigated how Npc1 deficiency impacts the absolute weight, lipid composition and histology of the lungs of Npc1−/− mice (Npc1nih) at different stages of the disease, and also quantitated changes in the rates of cholesterol and fatty acid synthesis in the lung over this same time span (8 to 70 days of age). Similar measurements were made in Npc2−/− mice at 70 days. All mice were of the BALB/c strain and were fed a basal rodent chow diet. Well before weaning, the lung weight, cholesterol and phospholipid (PL) content, and cholesterol synthesis rate were all elevated in the Npc1−/− mice and remained so at 70 days of age. In contrast, lung triacylglycerol content was reduced while there was no change in lung fatty acid synthesis. Despite the elevated PL content, the composition of PL in the lungs of the Npc1−/− mice was unchanged. H&E staining revealed an age-related increase in the presence of lipid-laden macrophages in the alveoli of the lungs of the Npc1−/− mice starting as early as 28 days. Similar metabolic and histologic changes were evident in the lungs of the Npc2−/− mice. Together these findings demonstrate an intrinsic lung pathology in NPC disease that is of early onset and worsens over time.

Impact of the loss of caveolin-1 on lung mass and cholesterol metabolism in mice with and without the lysosomal cholesterol transporter, Niemann–Pick type C1

“…3D) data reveal striking genotypic differences. The 2.8-fold greater cholesterol concentration in the lungs of Cav-1 +/+ : Npc1 −/− is in keeping with the known lung phenotype of Npc1-deficient mice [11]. Unexpectedly, the loss of Cav-1 function in the face of Npc1 deficiency led to a significantly higher total cholesterol concentration in the Cav-1 −/− : Npc1 −/− mice compared to that in their littermates deficient in just Npc1 (Fig.…”

“…Pulmonary dysfunction in Npc1 and Npc2 deficiency can itself be a cause of premature death [48]. Depending on a number of factors, including their strain background and the type of mutation in the Npc1 gene, the lifespan of Npc1 −/− mice is usually around 80 to 85 days [11, 49]. It is difficult to predict how the loss of Cav-1 function in the Npc1 model might alter its lifespan given that for Cav-1 −/− mice one study found a 50% reduction in lifespan, whereas another laboratory reported no detectable change [26, 50].…”

“…In LAL deficiency there is a pronounced increase in tissue cholesteryl ester content whereas loss of function of either Npc1 or Npc2 results in a continuing and highly detrimental expansion of tissue unesterified cholesterol content in all organs. LAL, Npc1 and Npc2 deficiency each result in a distinctive lung phenotype [7-11]. …”

Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin

“…Consequently, cholesterol accumulation in the LEs/Ls of NPC1-defi cient patients and mice is more pronounced in liver than in any other tissue ( 58,59 ). The lung is another tissue whose function is impaired in NPC disease ( 58,(60)(61)(62), and lipid-laden macrophages are abundant in the lungs of NPC-defi cient mice ( 63 ). Moreover, age-related retinal degeneration occurs in Npc1 Ϫ / Ϫ mice ( 64 ).…”

Extensive macrophage accumulation in young and old Niemann–Pick C1 model mice involves the alternative, M2, activation pathway and inhibition of macrophage apoptosis

“…Lung disease studied in the Npc1 nih/nih ( Npc1 −/− ) and Npc2 −/− mouse models and in the NPC1 cat model have shown that lung endothelial cells and type I pneumocytes are heavily laden with stored material [8,9]. In these models foamy macrophages are abundant within alveolar spaces and cholesterol and phospholipid levels are increased [7–10]. To our knowledge, there have been no in vivo studies examining cell proliferation/death in these lungs.…”