Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis

Nicole M. White, Dechen Jiang, James Burgess, Ilya R. Bederman, Stephen F. Previs, Thomas J. Kelley

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Determining how the regulation of cellular processes is impacted in cystic fibrosis (CF) is fundamental to understanding disease pathology and to identifying new therapeutic targets. In this study, unesterified cholesterol accumulation is observed in lung and trachea sections obtained from CF patients compared with non-CF tissues, suggesting an inherent flaw in cholesterol processing. An alternate staining method utilizing a fluorescent cholesterol probe also indicates improper lysosomal storage of cholesterol in CF cells. Excess cholesterol is also manifested by a significant increase in plasma membrane cholesterol content in both cultured CF cells and in nasal tissue excised from cftr-/- mice. Impaired intracellular cholesterol movement is predicted to stimulate cholesterol synthesis, a hypothesis supported by the observation of increased de novo cholesterol synthesis in lung and liver of cftr-/- mice compared with controls. Furthermore, pharmacological inhibition of cholesterol transport is sufficient to cause CF-like elevation in cytokine production in wild-type cells in response to bacterial challenge but has no effect in CF cells. These data demonstrate via multiple methods in both cultured and in vivo models that cellular cholesterol homeostasis is inherently altered in CF. This perturbation of cholesterol homeostasis represents a potentially important process in CF pathogenesis.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume292
Issue number2
DOIs
StatePublished - Feb 1 2007

Fingerprint

Cystic Fibrosis
Homeostasis
Cholesterol
Lung
Trachea
Fluorescent Dyes
Nose
Fibrosis
Cell Membrane
Observation
Pharmacology
Pathology
Staining and Labeling
Cytokines

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis. / White, Nicole M.; Jiang, Dechen; Burgess, James; Bederman, Ilya R.; Previs, Stephen F.; Kelley, Thomas J.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 292, No. 2, 01.02.2007.

Research output: Contribution to journalArticle

White, Nicole M. ; Jiang, Dechen ; Burgess, James ; Bederman, Ilya R. ; Previs, Stephen F. ; Kelley, Thomas J. / Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2007 ; Vol. 292, No. 2.
@article{f54f75323e294d0c8213c51b81f055f9,
title = "Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis",
abstract = "Determining how the regulation of cellular processes is impacted in cystic fibrosis (CF) is fundamental to understanding disease pathology and to identifying new therapeutic targets. In this study, unesterified cholesterol accumulation is observed in lung and trachea sections obtained from CF patients compared with non-CF tissues, suggesting an inherent flaw in cholesterol processing. An alternate staining method utilizing a fluorescent cholesterol probe also indicates improper lysosomal storage of cholesterol in CF cells. Excess cholesterol is also manifested by a significant increase in plasma membrane cholesterol content in both cultured CF cells and in nasal tissue excised from cftr-/- mice. Impaired intracellular cholesterol movement is predicted to stimulate cholesterol synthesis, a hypothesis supported by the observation of increased de novo cholesterol synthesis in lung and liver of cftr-/- mice compared with controls. Furthermore, pharmacological inhibition of cholesterol transport is sufficient to cause CF-like elevation in cytokine production in wild-type cells in response to bacterial challenge but has no effect in CF cells. These data demonstrate via multiple methods in both cultured and in vivo models that cellular cholesterol homeostasis is inherently altered in CF. This perturbation of cholesterol homeostasis represents a potentially important process in CF pathogenesis.",
author = "White, {Nicole M.} and Dechen Jiang and James Burgess and Bederman, {Ilya R.} and Previs, {Stephen F.} and Kelley, {Thomas J.}",
year = "2007",
month = "2",
day = "1",
doi = "10.1152/ajplung.00262.2006",
language = "English (US)",
volume = "292",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "2",

}

TY - JOUR

T1 - Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis

AU - White, Nicole M.

AU - Jiang, Dechen

AU - Burgess, James

AU - Bederman, Ilya R.

AU - Previs, Stephen F.

AU - Kelley, Thomas J.

PY - 2007/2/1

Y1 - 2007/2/1

N2 - Determining how the regulation of cellular processes is impacted in cystic fibrosis (CF) is fundamental to understanding disease pathology and to identifying new therapeutic targets. In this study, unesterified cholesterol accumulation is observed in lung and trachea sections obtained from CF patients compared with non-CF tissues, suggesting an inherent flaw in cholesterol processing. An alternate staining method utilizing a fluorescent cholesterol probe also indicates improper lysosomal storage of cholesterol in CF cells. Excess cholesterol is also manifested by a significant increase in plasma membrane cholesterol content in both cultured CF cells and in nasal tissue excised from cftr-/- mice. Impaired intracellular cholesterol movement is predicted to stimulate cholesterol synthesis, a hypothesis supported by the observation of increased de novo cholesterol synthesis in lung and liver of cftr-/- mice compared with controls. Furthermore, pharmacological inhibition of cholesterol transport is sufficient to cause CF-like elevation in cytokine production in wild-type cells in response to bacterial challenge but has no effect in CF cells. These data demonstrate via multiple methods in both cultured and in vivo models that cellular cholesterol homeostasis is inherently altered in CF. This perturbation of cholesterol homeostasis represents a potentially important process in CF pathogenesis.

AB - Determining how the regulation of cellular processes is impacted in cystic fibrosis (CF) is fundamental to understanding disease pathology and to identifying new therapeutic targets. In this study, unesterified cholesterol accumulation is observed in lung and trachea sections obtained from CF patients compared with non-CF tissues, suggesting an inherent flaw in cholesterol processing. An alternate staining method utilizing a fluorescent cholesterol probe also indicates improper lysosomal storage of cholesterol in CF cells. Excess cholesterol is also manifested by a significant increase in plasma membrane cholesterol content in both cultured CF cells and in nasal tissue excised from cftr-/- mice. Impaired intracellular cholesterol movement is predicted to stimulate cholesterol synthesis, a hypothesis supported by the observation of increased de novo cholesterol synthesis in lung and liver of cftr-/- mice compared with controls. Furthermore, pharmacological inhibition of cholesterol transport is sufficient to cause CF-like elevation in cytokine production in wild-type cells in response to bacterial challenge but has no effect in CF cells. These data demonstrate via multiple methods in both cultured and in vivo models that cellular cholesterol homeostasis is inherently altered in CF. This perturbation of cholesterol homeostasis represents a potentially important process in CF pathogenesis.

UR - http://www.scopus.com/inward/record.url?scp=33847026096&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33847026096&partnerID=8YFLogxK

U2 - 10.1152/ajplung.00262.2006

DO - 10.1152/ajplung.00262.2006

M3 - Article

C2 - 17085523

AN - SCOPUS:33847026096

VL - 292

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 2

ER -