title: ABCA3 protects alveolar epithelial cells against free cholesterol induced cell death.
abstract: Diffuse parenchymal lung diseases (DPLDs) are characterized by chronic inflammation and fibrotic remodeling of the interstitial tissue. A small fraction of DPLD cases can be genetically defined by mutations in certain genes, with ABCA3 being the gene most commonly affected. However, the pathomechanisms underlying ABCA3-induced DPLD are far from clear. To investigate whether ABCA3 plays a role in cellular cholesterol homeostasis, phospholipids, free cholesterol, and cholesteryl esters were quantified in cells stably expressing ABCA3 using mass spectrometry. Cellular free cholesterol and lipid droplets were visualized by filipin or oil red staining, respectively. Expression of SREBP regulated genes was measured using qPCR. Cell viability was assessed using the XTT assay. We found that wild type ABCA3 reduces cellular free cholesterol levels, induces the SREBP pathway, and renders cells more resistant to loading with exogenous cholesterol. Moreover, ABCA3 mutations found in patients with DPLD interfere with this protective effect of ABCA3, resulting in free cholesterol induced cell death. We conclude that ABCA3 plays a previously unrecognized role in the regulation of cellular cholesterol levels. Accumulation of free cholesterol as a result of a loss of ABCA3 export function represents a novel pathomechanism in ABCA3-induced DPLD.
authors: German Centre for Lung Research, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, 80337 Munich, Germany. Electronic address: Ralf.Zarbock@med.uni-muenchen.de.
authors: Ralf
authors: R
authors: Zarbock
authors: German Centre for Lung Research, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, 80337 Munich, Germany.
authors: Eva
authors: E
authors: Kaltenborn
authors: German Centre for Lung Research, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, 80337 Munich, Germany.
authors: Sabrina
authors: S
authors: Frixel
authors: German Centre for Lung Research, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, 80337 Munich, Germany.
authors: Thomas
authors: T
authors: Wittmann
authors: Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany.
authors: Gerhard
authors: G
authors: Liebisch
authors: Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany.
authors: Gerd
authors: G
authors: Schmitz
authors: German Centre for Lung Research, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, 80337 Munich, Germany.
authors: Matthias
authors: M
authors: Griese
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D056809:Alveolar Epithelial Cells / Q000187:drug effects* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics*; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D017563:Lung Diseases, Interstitial / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010743:Phospholipids / Q000378:metabolism / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000502:physiology*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000502:physiology
chemical_list: C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D010743:Phospholipids; D002784:Cholesterol
keywords: ABC transporter; ABCA3; Cholesterol; Diffuse parenchymal lung disease; Pulmonary surfactant