title: Role of CoA and acetyl-CoA in regulating cardiac fatty acid and glucose oxidation.
abstract: CoA (coenzyme A) and its derivatives have a critical role in regulating cardiac energy metabolism. This includes a key role as a substrate and product in the energy metabolic pathways, as well as serving as an allosteric regulator of cardiac energy metabolism. In addition, the CoA ester malonyl-CoA has an important role in regulating fatty acid oxidation, secondary to inhibiting CPT (carnitine palmitoyltransferase) 1, a key enzyme involved in mitochondrial fatty acid uptake. Alterations in malonyl-CoA synthesis by ACC (acetyl-CoA carboxylase) and degradation by MCD (malonyl-CoA decarboxylase) are important contributors to the high cardiac fatty acid oxidation rates seen in ischaemic heart disease, heart failure, obesity and diabetes. Additional control of fatty acid oxidation may also occur at the level of acetyl-CoA involvement in acetylation of mitochondrial fatty acid β-oxidative enzymes. We find that acetylation of the fatty acid β-oxidative enzymes, LCAD (long-chain acyl-CoA dehydrogenase) and β-HAD (β-hydroxyacyl-CoA dehydrogenase) is associated with an increase in activity and fatty acid oxidation in heart from obese mice with heart failure. This is associated with decreased SIRT3 (sirtuin 3) activity, an important mitochondrial deacetylase. In support of this, cardiac SIRT3 deletion increases acetylation of LCAD and β-HAD, and increases cardiac fatty acid oxidation. Acetylation of MCD is also associated with increased activity, decreases malonyl-CoA levels and an increase in fatty acid oxidation. Combined, these data suggest that malonyl-CoA and acetyl-CoA have an important role in mediating the alterations in fatty acid oxidation seen in heart failure.
authors.affiliation: *Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada, T6G 2S2.
authors.forename: Osama
authors.initials: O
authors.lastname: Abo Alrob
authors.affiliation: *Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada, T6G 2S2.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D002332:Carnitine O-Acetyltransferase / Q000378:metabolism; D003065:Coenzyme A / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D010084:Oxidation-Reduction; D056566:Sirtuin 3 / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D000105:Acetyl Coenzyme A; D002332:Carnitine O-Acetyltransferase; D056566:Sirtuin 3; D005947:Glucose; D008239:Lysine; D003065:Coenzyme A