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Impaired cholesterol transport as a mechanism for the cell signaling events in cystic fibrosis
Author(s) -
White Nicole M,
Kelley Thomas J
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a980-b
Subject(s) - cystic fibrosis , cholesterol , reverse cholesterol transport , abca1 , signal transduction , cystic fibrosis transmembrane conductance regulator , chemistry , endocrinology , microbiology and biotechnology , medicine , biology , biochemistry , lipoprotein , transporter , gene
Cystic fibrosis (CF) is caused by a loss of CFTR function causing severe lung disease. Functionally connecting CF‐related cell signaling pathway alterations to CFTR is a constant goal. We have shown that several inflammatory proteins exhibit altered expression patterns in models of CF epithelium. A commonality in these pathways is protein prenylation; a product of the isoprenoid/cholesterol pathway. We hypothesize that a loss of CFTR function causes impaired intracellular cholesterol transport resulting in increased isoprenoid/cholesterol synthesis and leading to CF‐related signaling events. Two models of CF exhibit increased content of unesterified cholesterol and accumulated free cholesterol. Preliminary staining of human CF trachea also indicates altered accumulation of cholesterol. Acutely inhibiting CFTR in control epithelial cells showed increased total cholesterol accumulation. CF mouse lung also had elevated cholesterol synthesis compared to matched controls. Alterations in calcium regulation have been identified in CF cells, as well as, previously implicated in cholesterol transport regulation. CF cells pretreated with GPN, a substrate that releases calcium, reverse the cholesterol accumulation in CF cell models. Intervention within cholesterol regulatory pathways may represent a novel therapeutic option for the treatment of CF. Supported by the CFF.