Linked Life Data

19713213

Source:http://linkedlifedata.com/resource/pubmed/id/19713213

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
45
pubmed:dateCreated
2009-11-2
pubmed:abstractText
12/15-Lipoxygenase (12/15LO) plays a role in the pathogenesis of atherosclerosis and diabetes and has been implicated in low density lipoprotein oxidation. Murine macrophages express high levels of 12/15LO and are key cells involved in the accumulation and efflux of oxidized low density lipoprotein in the arterial wall. During this process, macrophages up-regulate scavenger receptors that regulate lipid uptake, and ATP-binding cassette (ABC) transporters, that regulate lipid efflux. We have previously demonstrated that 12/15LO enhances the turnover and serine phosphorylation of ABCG1. In the current study, we further elucidate the mechanisms by which 12/15LO regulates ABCG1. Proteasomal inhibitors blocked the down-regulation of ABCG1 expression and resulted in accumulation of phosphorylated ABCG1. Macrophages that lack 12/15LO have enhanced transporter expression, reduced ABCG1 phosphorylation, and increased cholesterol efflux. Conversely, macrophages that overexpress 12/15LO have reduced ABCG1 expression, increased transporter phosphorylation, and reduced cholesterol efflux. 12/15LO plays a key role in activating the MAPK pathway. Inhibition of the p38 or JNK pathways with pharmacological inhibitors or dominant negative constructs blocked 12S-hydroxyeicosatetranoic acid-mediated degradation of ABCG1. Moreover, we isolated macrophages from JNK1-, JNK2-, and MKK3-deficient mice to analyze the involvement of specific MAPK pathways. JNK2- and MKK3-, but not JNK1-deficient macrophages were resistant to the down-regulation of ABCG1 protein, reduction in efflux, and increase in serine phosphorylation by 12S-hydroxyeicosatetranoic acid. These findings provide evidence that 12/15LO regulates ABCG1 expression and function through p38- and JNK2-dependent mechanisms, and that targeting these pathways may provide novel approaches for regulating cholesterol homeostasis.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1083-351X
pubmed:author
pubmed:issnType
Electronic
pubmed:day
6
pubmed:volume
284
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
31303-14
pubmed:dateRevised
2010-11-9
pubmed:meshHeading
pubmed-meshheading:19713213-ATP-Binding Cassette Transporters, pubmed-meshheading:19713213-Animals, pubmed-meshheading:19713213-Arachidonate 12-Lipoxygenase, pubmed-meshheading:19713213-Arachidonate 15-Lipoxygenase, pubmed-meshheading:19713213-Biological Transport, pubmed-meshheading:19713213-Female, pubmed-meshheading:19713213-Gene Expression Regulation, pubmed-meshheading:19713213-Lipid Metabolism, pubmed-meshheading:19713213-Lipoproteins, pubmed-meshheading:19713213-MAP Kinase Signaling System, pubmed-meshheading:19713213-Mice, pubmed-meshheading:19713213-Mice, Inbred C57BL, pubmed-meshheading:19713213-Mice, Knockout, pubmed-meshheading:19713213-Mice, Transgenic, pubmed-meshheading:19713213-Mitogen-Activated Protein Kinase 9, pubmed-meshheading:19713213-Phosphorylation, pubmed-meshheading:19713213-p38 Mitogen-Activated Protein Kinases
pubmed:year
2009
pubmed:articleTitle
Murine 12/15-lipoxygenase regulates ATP-binding cassette transporter G1 protein degradation through p38- and JNK2-dependent pathways.
pubmed:affiliation
Department of Pharmacology, The Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22908, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural