Document Detail

Macrophage fatty-acid synthase deficiency decreases diet-induced atherosclerosis.
MedLine Citation:
PMID:  20479009     Owner:  NLM     Status:  MEDLINE    
Fatty acid metabolism is perturbed in atherosclerotic lesions, but whether it affects lesion formation is unknown. To determine whether fatty acid synthesis affects atherosclerosis, we inactivated fatty-acid synthase (FAS) in macrophages of apoE-deficient mice. Serum lipids, body weight, and glucose metabolism were the same in FAS knock-out in macrophages (FASKOM) and control mice, but blood pressure was lower in FASKOM animals. Atherosclerotic extent was decreased 20-40% in different aortic regions of FASKOM as compared with control mice on Western diets. Foam cell formation was diminished in FASKOM as compared with wild type macrophages due to increased apoAI-specific cholesterol efflux and decreased uptake of oxidized low density lipoprotein. Expression of the anti-atherogenic nuclear receptor liver X receptor alpha (LXRalpha; Nr1h3) and its downstream targets, including Abca1, were increased in FASKOM macrophages, whereas expression of the potentially pro-atherogenic type B scavenger receptor CD36 was decreased. Peroxisome proliferator-activated receptor alpha (PPARalpha) target gene expression was decreased in FASKOM macrophages. PPARalpha agonist treatment of FASKOM and wild type macrophages normalized PPARalpha target gene expression as well as Nr1h3 (LXRalpha). Atherosclerotic lesions were more extensive when apoE null mice were transplanted with LXRalpha-deficient/FAS-deficient bone marrow as compared with LXRalpha-replete/FAS-deficient marrow, consistent with anti-atherogenic effects of LXRalpha in the context of FAS deficiency. These results show that macrophage FAS deficiency decreases atherosclerosis through induction of LXRalpha and suggest that FAS, which is induced by LXRalpha, may generate regulatory lipids that cause feedback inhibition of LXRalpha in macrophages.
Jochen G Schneider; Zhen Yang; Manu V Chakravarthy; Irfan J Lodhi; Xiaochao Wei; John Turk; Clay F Semenkovich
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-05-17
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-19     Completed Date:  2010-08-17     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  23398-409     Citation Subset:  IM    
Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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MeSH Terms
Apolipoproteins E / deficiency,  genetics
Atherosclerosis / enzymology*,  etiology*,  metabolism,  pathology
Diet / adverse effects*
Disease Susceptibility
Enzyme Activation
Fatty Acid Synthetase Complex / deficiency*,  genetics,  metabolism*
Gene Deletion
Gene Expression Regulation
Gene Knockout Techniques
Lipid Metabolism
Macrophages / enzymology*
Orphan Nuclear Receptors / deficiency
PPAR alpha / metabolism
Grant Support
Reg. No./Substance:
0/Apolipoproteins E; 0/Orphan Nuclear Receptors; 0/PPAR alpha; 0/liver X receptor; EC 6.-/Fatty Acid Synthetase Complex

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