title: Activation of sterol-response element-binding proteins (SREBP) in alveolar type II cells enhances lipogenesis causing pulmonary lipotoxicity.
abstract: Pulmonary inflammation is associated with altered lipid synthesis and clearance related to diabetes, obesity, and various inherited metabolic disorders. In many tissues, lipogenesis is regulated at the transcriptional level by the activity of sterol-response element-binding proteins (SREBP). The role of SREBP activation in the regulation of lipid metabolism in the lung was assessed in mice in which both Insig1 and Insig2 genes, encoding proteins that bind and inhibit SREBPs in the endoplasmic reticulum, were deleted in alveolar type 2 cells. Although deletion of either Insig1 or Insig2 did not alter SREBP activity or lipid homeostasis, deletion of both genes (Insig1/2(Δ/Δ) mice) activated SREBP1, causing marked accumulation of lipids that consisted primarily of cholesterol esters and triglycerides in type 2 epithelial cells and alveolar macrophages. Neutral lipids accumulated in type 2 cells in association with the increase in mRNAs regulating fatty acid, cholesterol synthesis, and inflammation. Although bronchoalveolar lavage fluid phosphatidylcholine was modestly decreased, lung phospholipid content and lung function were maintained. Insig1/2(Δ/Δ) mice developed lung inflammation and airspace abnormalities associated with the accumulation of lipids in alveolar type 2 cells, alveolar macrophages, and within alveolar spaces. Deletion of Insig1/2 activated SREBP-enhancing lipogenesis in respiratory epithelial cells resulting in lipotoxicity-related lung inflammation and tissue remodeling.
authors.affiliation: Section of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and.
authors.forename: Laurent
authors.initials: L
authors.lastname: Plantier
authors.affiliation: Section of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and.
authors.forename: Valérie
authors.initials: V
authors.lastname: Besnard
authors.affiliation: Section of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Section of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and.
authors.forename: Machiko
authors.initials: M
authors.lastname: Ikegami
authors.affiliation: Section of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Wert
authors.affiliation: Division of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Alan N
authors.initials: AN
authors.lastname: Hunt
authors.affiliation: Division of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Postle
authors.affiliation: Section of Neonatology, Perinatal and Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229 and. Electronic address: jeff.whitsett@cchmc.org.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
mesh_terms: D000818:Animals; D002788:Cholesterol Esters / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D050155:Lipogenesis; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011014:Pneumonia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism
chemical_list: D002788:Cholesterol Esters; C506119:Insig1 protein, mouse; C506120:Insig2 protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; D051779:Sterol Regulatory Element Binding Proteins; D014280:Triglycerides