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

Charina M. Ramirez, Adam M. Lopez, Lam Q. Le, Kenneth S. Posey, Arthur G. Weinberg, Stephen D. Turley

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 (Npc1 nih) 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.

Original languageEnglish (US)
Pages (from-to)54-61
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1841
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Type C Niemann-Pick Disease
Lipid Metabolism
Histology
Cholesterol
Lung
Phospholipids
Fatty Acids
Lipids
Weights and Measures
Neurologic Manifestations
Weaning
Rodentia
Triglycerides
Cell Death

Keywords

  • Alveoli
  • Liver
  • Phospholipid
  • Pulmonary
  • Triacylglycerol

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Ontogenic changes in lung cholesterol metabolism, lipid content, and histology in mice with Niemann-Pick type C disease. / Ramirez, Charina M.; Lopez, Adam M.; Le, Lam Q.; Posey, Kenneth S.; Weinberg, Arthur G.; Turley, Stephen D.

In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, Vol. 1841, No. 1, 2014, p. 54-61.

Research output: Contribution to journalArticle

@article{a396f39f27ee4b4a979d0a9cebfbb69c,
title = "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 (Npc1 nih) 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.",
keywords = "Alveoli, Liver, Phospholipid, Pulmonary, Triacylglycerol",
author = "Ramirez, {Charina M.} and Lopez, {Adam M.} and Le, {Lam Q.} and Posey, {Kenneth S.} and Weinberg, {Arthur G.} and Turley, {Stephen D.}",
year = "2014",
doi = "10.1016/j.bbalip.2013.09.010",
language = "English (US)",
volume = "1841",
pages = "54--61",
journal = "Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids",
issn = "1388-1981",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Ontogenic changes in lung cholesterol metabolism, lipid content, and histology in mice with Niemann-Pick type C disease

AU - Ramirez, Charina M.

AU - Lopez, Adam M.

AU - Le, Lam Q.

AU - Posey, Kenneth S.

AU - Weinberg, Arthur G.

AU - Turley, Stephen D.

PY - 2014

Y1 - 2014

N2 - 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 (Npc1 nih) 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.

AB - 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 (Npc1 nih) 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.

KW - Alveoli

KW - Liver

KW - Phospholipid

KW - Pulmonary

KW - Triacylglycerol

UR - http://www.scopus.com/inward/record.url?scp=84885342745&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84885342745&partnerID=8YFLogxK

U2 - 10.1016/j.bbalip.2013.09.010

DO - 10.1016/j.bbalip.2013.09.010

M3 - Article

VL - 1841

SP - 54

EP - 61

JO - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids

JF - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids

SN - 1388-1981

IS - 1

ER -