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

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

doi:10.1152/ajplung.00262.2006

Cited by 85 publications

(115 citation statements)

References 44 publications

(58 reference statements)

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“…Respiratory inflammation and increased expression of cytokines have been reported to increase in mice lacking functional lysosomal acid lipase, or following administration of a cholesterol-rich diet (11,12,62,63). Conversely, recent studies suggest a protective role of the cholesterol-lowering drugs statins in smoke-driven respiratory inflammation, COPD, and asthma in both mice (64 -67) and humans (68,69).…”

Section: Discussionmentioning

confidence: 99%

Loss of ABCG1 Results in Chronic Pulmonary Inflammation

Baldán

Gomes²,

Ping³

et al. 2008

The Journal of Immunology

115

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ABCG1, a member of the ATP-binding cassette transporter superfamily, is highly expressed in multiple cells of the lung. Loss of ABCG1 results in severe pulmonary lipidosis in mice, with massive deposition of cholesterol in both alveolar macrophages and type 2 cells and the accumulation of excessive surfactant phospholipids. These observations are consistent with ABCG1 controlling cellular sterol metabolism. Herein, we report on the progressive and chronic inflammatory process that accompanies the lipidosis in the lungs of Abcg1−/− mice. Compared with wild-type animals, the lungs of aged chow-fed mice deficient in ABCG1 show distinctive signs of inflammation that include macrophage accumulation, lymphocytic infiltration, hemorrhage, eosinophilic crystals, and elevated levels of numerous cytokines and cytokine receptors. Analysis of bronchoalveolar lavages obtained from Abcg1−/− mice revealed elevated numbers of foamy macrophages and leukocytes and the presence of multiple markers of inflammation including crystals of chitinase-3-like proteins. These data suggest that cholesterol and/or cholesterol metabolites that accumulate in Abcg1−/− lungs can trigger inflammatory signaling pathways. Consistent with this hypothesis, the expression of a number of cytokines was found to be significantly increased following increased cholesterol delivery to either primary peritoneal macrophages or Raw264.7 cells. Finally, cholesterol loading of primary mouse macrophages induced cytokine mRNAs to higher levels in Abcg1−/−, as compared with wild-type cells. These results demonstrate that ABCG1 plays critical roles in pulmonary homeostasis, balancing both lipid/cholesterol metabolism and inflammatory responses.

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Section: Discussionmentioning

confidence: 99%

Loss of ABCG1 Results in Chronic Pulmonary Inflammation

Baldán

Gomes²,

Ping³

et al. 2008

The Journal of Immunology

115

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“…Cholesterol synthesis measurements were performed as described ( 11 ). Briefl y, mice and the matched controls were given an intraperitoneal injection ( ‫ف‬ 24 µl per g body weight) of deuterated saline (9 g NaCl in 1,000 ml of 99% 2 H 2 O; Sigma-Aldrich, St. Louis, MO).…”

Section: Measuring Cholesterol Synthesis In Vivomentioning

confidence: 99%

“…There are three different manifestations of the CF cholesterol phenotype: perinuclear free-cholesterol accumulation, increased membrane cholesterol content, and increased de novo cholesterol synthesis ( 10,11 ). Previously we demonstrated that accumulated perinuclear cholesterol in CF-cell models is reversible in the presence of the cAMP binding competitor Rp -cAMPS, and it colocalizes with internalized ␤ 2-adrenergic receptor ( ␤ 2-AR) ( 12 ).…”

mentioning

confidence: 99%

“…resulting in dysregulation of ion transport, abnormal infl ammatory response signaling, and altered cholesterol homeostasis both in CF-cell models and in vivo (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). There are three different manifestations of the CF cholesterol phenotype: perinuclear free-cholesterol accumulation, increased membrane cholesterol content, and increased de novo cholesterol synthesis ( 10,11 ).…”

mentioning

confidence: 99%

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Regulatory role of β-arrestin-2 in cholesterol processing in cystic fibrosis epithelial cells

Manson

Corey

Bederman

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org resulting in dysregulation of ion transport, abnormal infl ammatory response signaling, and altered cholesterol homeostasis both in CF-cell models and in vivo ( 1-11 ). There are three different manifestations of the CF cholesterol phenotype: perinuclear free-cholesterol accumulation, increased membrane cholesterol content, and increased de novo cholesterol synthesis ( 10,11 ). Previously we demonstrated that accumulated perinuclear cholesterol in CF-cell models is reversible in the presence of the cAMP binding competitor Rp -cAMPS, and it colocalizes with internalized ␤ 2-adrenergic receptor ( ␤ 2-AR) ( 12 ). These fi ndings implicate the arrestin/G-protein coupled receptor kinase (GRK) pathway as a potential regulator of the CF cholesterol phenotype. The same study demonstrated increased expression of ␤ -arrestin-2 ( ␤ arr2) in CFcell models, Cftr Ϫ / Ϫ mouse nasal epithelia (MNE), and nasal scrapes obtained from CF patients compared with respective controls ( 12 ). The hypothesis to test in this study is that expression of ␤ arr2 in CF cells mediates the development of Rp -cAMPS -sensitive cholesterol accumulation. Arrestins are multifunctional proteins that infl uence several cell regulatory pathways. The function initially identifi ed was as regulators of G-protein coupled receptors (GPCR) in concert with GRKs. Arrestins and GRKs act as silencers of a variety of GPCRs, such as ␤ -adrenergic receptors ( ␤ -AR), rhodopsin, and CXCRs ( 13 ). Phosphorylated by GRKs, arrestins bind to GPCRs, inhibiting interactions with G-protein subunits and stimulating receptor internalization ( 6 ). In addition to the regulation of GPCRs, arrestins have been linked to cell signaling regulation, and they affect the activity of c-Src, RhoA, PI3 kinase, MAPKs, and NF-B ( 14-17 ). Arrestin-and GRK-mediated internalization of receptors utilizes the late endosomal/lysosomal Abbreviations: ␤ 2-AR, ␤ 2-adrenergic receptor; ␤ arr2, ␤ -arrestin-2; ␤ arr2-GFP, GFP-tagged ␤ arr2 cell; CF, cystic fi brosis; CFTR, cystic fi brosis transmembrane conductance regulator; DKO, double knockout; cont-GFP, GFP-expressing control cell; GPCR, G-protein coupled receptor; GRK, G-protein coupled receptor kinase; MNE, mouse nasal epithelia; NOS2, nitric oxide synthase 2; NPC1, Niemann-Pick type C-1; WT , wild-type.

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“…In these patients, altered fatty acid levels including reduced levels of docosahexaenoic acid [28] have been described and docosahexaenoic acid supplementation improved the clinical status in some studies [29] . Other lipid anomalies in cystic fibrosis are altered cholesterol homeostasis [30] , and elevated cholesteryl ester concentrations in tracheobronchial secretions [31] . We have found an increased cholesteryl ester representation in the lipid content of bronchoalveolar lavages obtained from pediatric cystic fibrosis patients [32] .…”

Section: Airwaysmentioning

confidence: 99%

Antimicrobial lipids: Emerging effector molecules of innate host defense

Porter

Daniel²,

Alvarez³

et al. 2015

WJI

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The antimicrobial properties of host-derived derived lipids have become increasingly recognized and evidence is mounting that antimicrobial lipids (AMLs), like antimicrobial peptides, are effector molecules of the innate immune system and are regulated by its conserved pathways. This review, with primary focus on the human body, provides some background on the biochemistry of lipids, summarizes their biological functions, expands on their antimicrobial properties and site-specific composition, presents modes of synergism with antimicrobial peptides, and highlights the more recent reports on the regulation of AML production as well as bacterial resistance mechanisms. Based on extant data a concept of innate epithelial defense is proposed where epithelial cells, in response to microbial products and proinflammatory cytokines and through activation of conserved innate signaling pathways, increase their lipid uptake and up-regulate transcription of enzymes involved in antimicrobial lipid biosynthesis, and induce transcription of antimicrobial peptides as well as cytokines and chemokines. The subsequently secreted antimicrobial peptides and lipids then attack and eliminate the invader, assisted by or in synergism with other antimicrobial molecules delivered by other defense cells that have been recruited to the site of infection, in most of the cases. This review invites

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

Abstract: White NM, Jiang D, Burgess JD, Bederman IR, Previs SF, Kelley TJ. Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis.

Cited by 85 publications

References 44 publications

Loss of ABCG1 Results in Chronic Pulmonary Inflammation

Loss of ABCG1 Results in Chronic Pulmonary Inflammation

Regulatory role of β-arrestin-2 in cholesterol processing in cystic fibrosis epithelial cells

Antimicrobial lipids: Emerging effector molecules of innate host defense

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