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

Activation of sterol response element binding proteins (SREBP) in alveolar type II cells enhances lipogenesis causing pulmonary lipotoxicity
Activation of sterol response element binding proteins (SREBP) in alveolar type II cells enhances lipogenesis causing pulmonary lipotoxicity
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.
0021-9258
Plantier, Laurent
17d0b364-e045-45bd-94a9-244acf18da10
Besnard, Valerie
39b843ae-0b82-440e-8bfc-191cf6d8619c
Xu, Yan
2b4952f1-3855-4a5d-a8b0-777561a292e1
Ikegami, Machiko
24da55aa-037b-4900-b817-691033d39ffc
Wert, Susan E
c8deba05-b3de-4bad-9acc-b2cb874f9327
Hunt, Alan N
95a3e223-da96-40e7-b47d-27dce014e305
Postle, Anthony D
0fa17988-b4a0-4cdc-819a-9ae15c5dad66
Whitsett, Jeffrey A
16b735e4-2a08-4696-9bb9-588c19bf5c13
Plantier, Laurent
17d0b364-e045-45bd-94a9-244acf18da10
Besnard, Valerie
39b843ae-0b82-440e-8bfc-191cf6d8619c
Xu, Yan
2b4952f1-3855-4a5d-a8b0-777561a292e1
Ikegami, Machiko
24da55aa-037b-4900-b817-691033d39ffc
Wert, Susan E
c8deba05-b3de-4bad-9acc-b2cb874f9327
Hunt, Alan N
95a3e223-da96-40e7-b47d-27dce014e305
Postle, Anthony D
0fa17988-b4a0-4cdc-819a-9ae15c5dad66
Whitsett, Jeffrey A
16b735e4-2a08-4696-9bb9-588c19bf5c13

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

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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

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Date deposited: 25 Jan 2012 11:49
Last modified: 15 Mar 2024 02:49

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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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