Document Detail


Mouse cardiac acyl coenzyme a synthetase 1 deficiency impairs Fatty Acid oxidation and induces cardiac hypertrophy.
MedLine Citation:
PMID:  21245374     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Long-chain acyl coenzyme A (acyl-CoA) synthetase isoform 1 (ACSL1) catalyzes the synthesis of acyl-CoA from long-chain fatty acids and contributes the majority of cardiac long-chain acyl-CoA synthetase activity. To understand its functional role in the heart, we studied mice lacking ACSL1 globally (Acsl1(T-/-)) and mice lacking ACSL1 in heart ventricles (Acsl1(H-/-)) at different times. Compared to littermate controls, heart ventricular ACSL activity in Acsl1(T-/-) mice was reduced more than 90%, acyl-CoA content was 65% lower, and long-chain acyl-carnitine content was 80 to 90% lower. The rate of [(14)C]palmitate oxidation in both heart homogenate and mitochondria was 90% lower than in the controls, and the maximal rates of [(14)C]pyruvate and [(14)C]glucose oxidation were each 20% higher. The mitochondrial area was 54% greater than in the controls with twice as much mitochondrial DNA, and the mRNA abundance of Pgc1α and Errα increased by 100% and 41%, respectively. Compared to the controls, Acsl1(T-/-) and Acsl1(H-/-) hearts were hypertrophied, and the phosphorylation of S6 kinase, a target of mammalian target of rapamycin (mTOR) kinase, increased 5-fold. Our data suggest that ACSL1 is required to synthesize the acyl-CoAs that are oxidized by the heart, and that without ACSL1, diminished fatty acid (FA) oxidation and compensatory catabolism of glucose and amino acids lead to mTOR activation and cardiac hypertrophy without lipid accumulation or immediate cardiac dysfunction.
Authors:
Jessica M Ellis; Shannon M Mentock; Michael A Depetrillo; Timothy R Koves; Shiraj Sen; Steven M Watkins; Deborah M Muoio; Gary W Cline; Heinrich Taegtmeyer; Gerald I Shulman; Monte S Willis; Rosalind A Coleman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-01-18
Journal Detail:
Title:  Molecular and cellular biology     Volume:  31     ISSN:  1098-5549     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-02-25     Completed Date:  2011-04-21     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1252-62     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Acyl Coenzyme A / metabolism
Animals
Cardiomegaly / metabolism*
Coenzyme A Ligases / genetics,  metabolism*
Fatty Acids / metabolism*
Gene Deletion
Glucose / metabolism
Lipid Metabolism
Mice
Myocardium / enzymology*,  metabolism
Oxidation-Reduction
TOR Serine-Threonine Kinases / metabolism
Grant Support
ID/Acronym/Agency:
DK056350/DK/NIDDK NIH HHS; DK59935/DK/NIDDK NIH HHS; P30 DK034989/DK/NIDDK NIH HHS; P30 ES010126/ES/NIEHS NIH HHS; R01 DK040936/DK/NIDDK NIH HHS; R01 DK059935/DK/NIDDK NIH HHS; R01 HL061483/HL/NHLBI NIH HHS; R01 HL061483-09/HL/NHLBI NIH HHS; R01 HL061483-11/HL/NHLBI NIH HHS; R01 HL104129/HL/NHLBI NIH HHS; T32-HL069768/HL/NHLBI NIH HHS; U24 DK059635/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Acyl Coenzyme A; 0/Fatty Acids; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.1.1/mTOR protein, mouse; EC 6.2.1.-/ACSL1 protein, mouse; EC 6.2.1.-/Coenzyme A Ligases; IY9XDZ35W2/Glucose
Comments/Corrections

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