NDLI: Activation of Sterol-response Element-binding Proteins (SREBP) in Alveolar Type II Cells Enhances Lipogenesis Causing Pulmonary Lipotoxicity

Content Provider	Journal of Biological Chemistry (JBC)
Author	Plantier, Laurent Besnard, Valérie Xu, Yan Ikegami, Machiko Wert, Susan E. Hunt, Alan N. Postle, Anthony D. Whitsett, Jeffrey A.
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 (Insig1/2Δ/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. Insig1/2Δ/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.
Related Links	http://www.jbc.org/content/287/13/10099.abstract
Ending Page	10114
Starting Page	10099
Page Count	16
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	13
Volume Number	287
DOI	10.1074/jbc.M111.303669
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2012-03-23
Access Restriction	Open
Subject Keyword	Inflammation Insulin Lipids Lipid Synthesis Lung Insulin-induced Gene Lipid Storage Lung Inflammation Metabolism
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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