title: Macrophage 12/15 lipoxygenase expression increases plasma and hepatic lipid levels and exacerbates atherosclerosis.
abstract: 12/15 lipoxygenase (12/15LO) oxidizes polyunsaturated fatty acids (PUFAs) to form bioactive lipid mediators. The role of 12/15LO in atherosclerosis development remains controversial. We evaluated atherosclerosis development and lipid metabolism in 12/15LO-LDL receptor (LDLr) double knockout (DK) vs. LDLr knockout (SK) mice fed a PUFA-enriched diet to enhance production of 12/15LO products. Compared with SK controls, DK mice fed a PUFA-enriched diet had decreased plasma and liver lipid levels, hepatic lipogenic gene expression, VLDL secretion, and aortic atherosclerosis and increased VLDL turnover. Bone marrow transplantation and Kupffer cell ablation studies suggested both circulating leukocytes and Kupffer cells contributed to the lipid phenotype in 12/15LO-deficient mice. Conditioned medium from in vitro incubation of DK vs. SK macrophages reduced triglyceride secretion in McArdle 7777 hepatoma cells. Our results suggest that, in the context of dietary PUFA enrichment, macrophage 12/15LO expression adversely affects plasma and hepatic lipid metabolism, resulting in exacerbated atherosclerosis.
authors.affiliation: Department of Pathology/Section on Lipid Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Shunxing
authors.initials: S
authors.lastname: Rong
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cao
authors.forename: Mingxia
authors.initials: M
authors.lastname: Liu
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Seo
authors.forename: Lin
authors.initials: L
authors.lastname: Jia
authors.forename: Elena
authors.initials: E
authors.lastname: Boudyguina
authors.forename: Abraham K
authors.initials: AK
authors.lastname: Gebre
authors.forename: Perry L
authors.initials: PL
authors.lastname: Colvin
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Smith
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.forename: Nilamadhab
authors.initials: N
authors.lastname: Mishra
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D050197:Atherosclerosis / Q000473:pathology*; D016026:Bone Marrow Transplantation; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D017077:Culture Media, Conditioned; D004036:Diet, Atherogenic / Q000009:adverse effects; D004042:Dietary Fats, Unsaturated / Q000008:administration & dosage; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D050356:Lipid Metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000473:pathology
chemical_list: C475064:12-15-lipoxygenase; D017077:Culture Media, Conditioned; D004042:Dietary Fats, Unsaturated; D005231:Fatty Acids, Unsaturated; D008079:Lipoproteins, VLDL; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase