title: Mechanistic similarities between cultured cell models of cystic fibrosis and niemann-pick type C.
abstract: Recent data demonstrate that inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase restores normal signal transducer and activator of transcription-1 and inducible nitric oxide synthase expression regulation in cystic fibrosis (CF) cells through the modulation of RhoA function. These findings lead to the hypothesis that alterations in the cholesterol synthesis pathway may be an initiating factor in CF-related cell signaling regulation. A disease with a known lesion in the cholesterol synthesis pathway is Niemann-Pick type C (NPC). The hypothesis of this study is that CF cells and NPC fibroblasts share a common mechanistic lesion and should exhibit similar cell signaling alterations. NPC fibroblasts exhibit similar alterations in signal transducer and activator of transcription-1, RhoA, SMAD3, and nitric oxide synthase protein expression that characterize CF. Further comparison reveals NPC-like accumulation of free cholesterol in two cultured models of CF epithelial cells. These data identify novel signaling changes in NPC, demonstrate the cholesterol-synthesis pathway is a likely source of CF-related cell signaling changes, and that cultured CF cells exhibit impaired cholesterol processing.
authors.affiliation: Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio 44106-4948, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: White
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Corey
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kelley
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D003550:Cystic Fibrosis / Q000201:enzymology*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D005372:Filipin / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009542:Niemann-Pick Diseases / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013696:Temperature; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D012333:RNA, Messenger; D005372:Filipin; D002784:Cholesterol; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; D020742:rhoA GTP-Binding Protein