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Activation of sterol response element binding proteins (SREBP) in alveolar type II cells enhances lipogenesis causing pulmonary lipotoxicity

Plantier, Laurent, Besnard, Valerie, Xu, Yan, Ikegami, Machiko, Wert, Susan E, Hunt, Alan N, Postle, Anthony D and Whitsett, Jeffrey A (2012) Activation of sterol response element binding proteins (SREBP) in alveolar type II cells enhances lipogenesis causing pulmonary lipotoxicity The Journal of Biological Chemistry (doi:10.1074/jbc.M111.303669). (PMID:22267724).

Record type: Article

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, proteins that bind and inhibit SREBPs in the endoplasmic reticulum, were deleted in alveolar type 2 cells. While deletion of either Insig1 or Insig2 did not alter SREBP activity or lipid homeostasis, deletion of both Insig proteins (Insig1/2(/) 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. While bronchoalveolar lavage fluid (BALF) phosphatidylcholine (PC) was modestly decreased, lung phospholipid content and lung function were maintained. Insig1/2(/) 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.

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More information

Published date: 20 January 2012
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 209039
URI: http://eprints.soton.ac.uk/id/eprint/209039
ISSN: 0021-9258
PURE UUID: c511117f-aaeb-4900-b22f-90a78566625e
ORCID for Alan N Hunt: ORCID iD orcid.org/0000-0001-5938-2152
ORCID for Anthony D Postle: ORCID iD orcid.org/0000-0001-7361-0756

Catalogue record

Date deposited: 25 Jan 2012 11:49
Last modified: 18 Jul 2017 10:47

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Contributors

Author: Laurent Plantier
Author: Valerie Besnard
Author: Yan Xu
Author: Machiko Ikegami
Author: Susan E Wert
Author: Alan N Hunt ORCID iD
Author: Jeffrey A Whitsett

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