| 12/15-Lipoxygenase activity increases the degradation of macrophage ATP-binding cassette transporter G1. | |
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MedLine Citation:
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PMID: 18635820 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: The purpose of this study was to evaluate the effect of 12/15-lipoxygenase (12/15LO) in macrophage ABCG1 expression and function associated with cholesterol efflux. METHODS AND RESULTS: 12/15LO was stably overexpressed in J774 macrophages. 12/15LO-overexpressing macrophages had a 30% reduction in HDL-mediated cholesterol efflux, corresponding with significantly reduced ABCG1 protein expression. Treatment of 12/15LO-overexpressing macrophages with a 12/15LO ribozyme to reduce 12/15LO restored HDL-mediated efflux and ABCG1 protein expression. Treating macrophages with 12/15LO unsaturated fatty acid substrates or eicosanoid products also reduced HDL-mediated cholesterol efflux. Additionally, both 12/15LO overexpression in macrophages and incubation of macrophages with eicosanoids reduced ABCG1 protein, but not mRNA, expression. However, incubation of macrophages with linoleic or arachidonic acids significantly reduced both ABCG1 mRNA and protein expression, suggesting that 12/15LO substrates and eicosanoid products differentially regulate ABCG1 expression. 12/15LO fatty acids did not decrease ABCG1 translation; however, 12/15LO fatty acids increased ABCG1 degradation when blocked by cyclohexidmide. ABCG1 degradation may be regulated through posttranslational modifications. Treatment with the 12/15LO eicosanoid product 12SHETE increased serine phosphorylation of ABCG1. CONCLUSIONS: We conclude that serine phosphorylation may increase the degradation rate of ABCG1, and as a result cause macrophage cholesterol accumulation. These findings provide evidence that 12/15LO activity in the vessel wall contributes to atherogenesis by impairing the macrophage ABCG1 cholesterol efflux pathway. |
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Authors:
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Melissa H Nagelin; Suseela Srinivasan; Jianyi Lee; Jerry L Nadler; Catherine C Hedrick |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2008-07-17 |
Journal Detail:
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Title: Arteriosclerosis, thrombosis, and vascular biology Volume: 28 ISSN: 1524-4636 ISO Abbreviation: Arterioscler. Thromb. Vasc. Biol. Publication Date: 2008 Oct |
Date Detail:
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Created Date: 2008-09-18 Completed Date: 2008-10-09 Revised Date: 2012-02-28 |
Medline Journal Info:
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Nlm Unique ID: 9505803 Medline TA: Arterioscler Thromb Vasc Biol Country: United States |
Other Details:
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Languages: eng Pagination: 1811-9 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, The Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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ATP-Binding Cassette Transporters
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genetics,
metabolism* Animals Arachidonate 12-Lipoxygenase / genetics, metabolism* Arachidonate 15-Lipoxygenase / genetics, metabolism* Arachidonic Acid / metabolism Cell Line Cholesterol, HDL / metabolism Down-Regulation Linoleic Acid / metabolism Lipoproteins / genetics, metabolism* Macrophages / enzymology* Mice Phosphorylation Protein Processing, Post-Translational* RNA, Catalytic / metabolism RNA, Messenger / metabolism Serine Swine Time Factors Transfection |
| Grant Support | |
ID/Acronym/Agency:
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P01 HL055798-130002/HL/NHLBI NIH HHS; P01 HL55798/HL/NHLBI NIH HHS; R01 HL085790/HL/NHLBI NIH HHS; R01 HL085790-02/HL/NHLBI NIH HHS; R01 HL085790-04/HL/NHLBI NIH HHS; R01 HL085790-05/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/12-15-lipoxygenase; 0/ABCG1 protein, mouse; 0/ATP-Binding Cassette Transporters; 0/Cholesterol, HDL; 0/Lipoproteins; 0/RNA, Catalytic; 0/RNA, Messenger; 2197-37-7/Linoleic Acid; 506-32-1/Arachidonic Acid; 56-45-1/Serine; EC 1.13.11.31/Arachidonate 12-Lipoxygenase; EC 1.13.11.33/Arachidonate 15-Lipoxygenase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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