Document Detail


Inhibition of long-chain acyl coenzyme A synthetases during fatty acid loading induces lipotoxicity in macrophages.
MedLine Citation:
PMID:  19679826     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Obesity is often associated with hypertriglyceridemia and elevated free fatty acids (FFAs), which are independent risk factors for cardiovascular disease and diabetes. Although impairment of cholesterol homeostasis is known to induce toxicity in macrophages, the consequence of altered fatty acid homeostasis is not clear.
METHODS AND RESULTS: Long-chain acyl CoA synthetases (ACSLs) play a critical role in fatty acid homeostasis by channeling fatty acids to diverse metabolic pools. We treated mouse peritoneal macrophages (MPMs) with VLDL or FFAs in the presence of triacsin C, an inhibitor of the 3 ACSL isoforms present in macrophages. Treatment of macrophages with VLDL and triacsin C resulted in reduced TG accumulation but increased intracellular FFA levels, which induced lipotoxicity characterized by apoptosis. Treatment of MPMs with the saturated fatty acid stearic acid in the presence of triacsin C increased intracellular stearic acid and induced apoptosis. Stromal vascular cells collected from high-fat diet-fed mice displayed foam cell morphology and exhibited increased mRNA levels of macrophage markers and ACSL1. Importantly, all of these changes were associated with increased FFA level in AT.
CONCLUSIONS: Inhibition of ACSLs during fatty acid loading results in apoptosis via accumulation of FFAs. Our data have implications in understanding the consequences of dysregulated fatty acid metabolism in macrophages.
Authors:
Viswanathan Saraswathi; Alyssa H Hasty
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural     Date:  2009-08-13
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  29     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-10-22     Completed Date:  2010-02-04     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1937-43     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects,  physiology
Cell Survival
Cells, Cultured
Cholesterol, VLDL / metabolism,  pharmacology
Coenzyme A Ligases / antagonists & inhibitors*,  metabolism
Fatty Acids, Nonesterified / metabolism*,  pharmacology
Lipid Metabolism / drug effects,  physiology*
Macrophages, Peritoneal / drug effects,  metabolism*
Mice
Sensitivity and Specificity
Triazenes / pharmacology
Grant Support
ID/Acronym/Agency:
HL089466/HL/NHLBI NIH HHS; R01 HL089466/HL/NHLBI NIH HHS; R01 HL089466-03/HL/NHLBI NIH HHS; R01 HL089466-05/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cholesterol, VLDL; 0/Fatty Acids, Nonesterified; 0/Triazenes; 76896-80-5/triacsin C; EC 6.2.1.-/Coenzyme A Ligases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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