Mouse Cardiac Acyl Coenzyme A Synthetase 1 Deficiency Impairs Fatty Acid Oxidation and Induces Cardiac Hypertrophy

Department of Nutrition, CB 7461, University of North Carolina at Chapel Hill, 135 Dauer Drive, MHRC 2301, Chapel Hill, NC 27599, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 02/2011; 31(6):1252-62. DOI: 10.1128/MCB.01085-10
Source: PubMed


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 (Acsl1T−/−) and mice lacking ACSL1 in heart ventricles (Acsl1H−/−) at different times. Compared to littermate controls, heart ventricular ACSL activity in Acsl1T−/− 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 [14C]palmitate oxidation in both heart homogenate and mitochondria was 90% lower than in the controls, and the maximal rates
of [14C]pyruvate and [14C]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, Acsl1T−/− and Acsl1H−/− 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.

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Available from: Steven M Watkins, Mar 06, 2014
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    • "The amount of mitochondrial DNA was quantified using quantitative PCR as described previously [13]. Total DNA was isolated using a QIAmp DNA microkit (Qiagen, Venlo, Netherlands). "
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    • "We observe gene expression remodeling due to loss of SRC-2 in both the metabolic and sarcomeric pathways implying that SRC-2 is an important upstream regulator of both of these key cardiac pathways. While expression of the metabolic fetal gene profile in the adult mouse heart has been previously shown in response to loss of a metabolic enzyme itself, such as Acsl1 [42], or loss of a upstream regulator of metabolic enzyme expression such as loss of the PPAR family of transcription factors [43], complete remodeling of both the metabolic and sarcomeric gene expression programs has not been reported under unstressed conditions. Furthermore, we observed decreased expression of several cardiac transcription factors in the SRC-2 KO hearts, many of which have been previously characterized to regulate metabolism or sarcomeric gene expression, but usually not both. "
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    • "ACSL1 is highly expressed in major energy-metabolizing tissues such as fat, liver, and skeletal muscles [5], [6]. Recent research also supports evidence for an important role of ACSL1 in heart metabolism [14]. "
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