Document Detail


Stearic acid accumulation in macrophages induces toll-like receptor 4/2-independent inflammation leading to endoplasmic reticulum stress-mediated apoptosis.
MedLine Citation:
PMID:  22556332     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Elevated serum free fatty acid levels are associated with an increased risk of cardiovascular disease and type 2 diabetes mellitus. Macrophages are recruited to atherosclerotic plaques and metabolic tissues during obesity and accumulate lipids, including free fatty acids. We investigated the molecular consequences of intracellular saturated free fatty acid accumulation in macrophages.
METHODS AND RESULTS: Previously, we demonstrated that cotreatment of mouse peritoneal macrophages (MPMs) with stearic acid and triacsin C (an inhibitor of long-chain acyl coenzyme A synthetases) results in intracellular free fatty acid accumulation and apoptosis. Here, we used Western blotting analysis, real-time reverse transcription polymerase chain reaction, and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining to assess endoplasmic reticulum (ER) stress, inflammation, and apoptosis in MPMs. Intracellular stearic acid accumulation induces Toll-like receptor 4/2-independent inflammation that results in ER stress-mediated apoptosis of MPMs. Polarization of MPMs to a proinflammatory M1 phenotype increases their susceptibility to inflammation and ER stress, but not apoptosis, in response to cotreatment with stearic acid and triacsin C.
CONCLUSIONS: Intracellular accumulation of stearic acid in MPMs activates inflammatory signaling, leading to ER stress-mediated apoptosis. M1 macrophages are more prone to stearic acid-induced inflammation and ER stress. These same pathways may be activated in macrophages residing in atherosclerotic plaques and metabolic tissues during conditions of obesity and hyperlipidemia.
Authors:
Emily K Anderson; Andrea A Hill; Alyssa H Hasty
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-03
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  32     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-06-15     Completed Date:  2012-08-23     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1687-95     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis*
Cell Polarity
Endoplasmic Reticulum Stress / physiology*
Inflammation / etiology*
Macrophages / metabolism*
Mice
Mice, Inbred C57BL
Stearic Acids / metabolism*
Toll-Like Receptor 2 / physiology
Toll-Like Receptor 4 / physiology
Grant Support
ID/Acronym/Agency:
CA68485/CA/NCI NIH HHS; DK20593/DK/NIDDK NIH HHS; DK58404/DK/NIDDK NIH HHS; DK59637/DK/NIDDK NIH HHS; EY08126/EY/NEI NIH HHS; HD15052/HD/NICHD NIH HHS; HL089466/HL/NHLBI NIH HHS; R01 HL089466/HL/NHLBI NIH HHS; R25 GM062459/GM/NIGMS NIH HHS; T32 HL007411/HL/NHLBI NIH HHS; T32 HL007411-30/HL/NHLBI NIH HHS; T32GM008554/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Stearic Acids; 0/Tlr2 protein, mouse; 0/Tlr4 protein, mouse; 0/Toll-Like Receptor 2; 0/Toll-Like Receptor 4; 4ELV7Z65AP/stearic acid
Comments/Corrections

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