Mouse cardiac acyl coenzyme a synthetase 1 deficiency impairs Fatty Acid oxidation and induces cardiac hypertrophy.
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.
Department of Nutrition, CB 7461, University of North Carolina at Chapel Hill, 135 Dauer Drive, MHRC 2301, Chapel Hill, NC 27599, USA.
Jessica M
JM
Ellis
Shannon M
SM
Mentock
Michael A
MA
Depetrillo
Timothy R
TR
Koves
Shiraj
S
Sen
Steven M
SM
Watkins
Deborah M
DM
Muoio
Gary W
GW
Cline
Heinrich
H
Taegtmeyer
Gerald I
GI
Shulman
Monte S
MS
Willis
Rosalind A
RA
Coleman
D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism*; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D010084:Oxidation-Reduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D000214:Acyl Coenzyme A; D005227:Fatty Acids; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; C544400:ACSL1 protein, mouse; D003066:Coenzyme A Ligases; D005947:Glucose
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