Role of CoA and acetyl-CoA in regulating cardiac fatty acid and glucose oxidation

2014 ◽  
Vol 42 (4) ◽  
pp. 1043-1051 ◽  
Author(s):  
Osama Abo Alrob ◽  
Gary D. Lopaschuk
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Oxidative Enzymes ◽  
Acid Oxidation ◽  
Acetyl Coa ◽  
Malonyl Coa ◽  
Mitochondrial Fatty Acid ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

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.

scholarly journals Peroxisomal Fatty Acid Oxidation Is a Substantial Source of the Acetyl Moiety of Malonyl-CoA in Rat Heart

2004 ◽  
Vol 279 (19) ◽  
pp. 19574-19579 ◽  
Author(s):  
Aneta E. Reszko ◽  
Takhar Kasumov ◽  
France David ◽  
Kathryn A. Jobbins ◽  
Katherine R. Thomas ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Acetyl Coa ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Fatty Acid Chain ◽  
Rat Hearts ◽  
Malonyl Coa ◽  
Mitochondrial Fatty Acid ◽  
Perfused Rat Hearts

Little is known about the sources of acetyl-CoA used for the synthesis of malonyl-CoA, a key regulator of mitochondrial fatty acid oxidation in the heart. In perfused rat hearts, we previously showed that malonyl-CoA is labeled from both carbohydrates and fatty acids. This study was aimed at assessing the mechanisms of incorporation of fatty acid carbons into malonyl-CoA. Rat hearts were perfused with glucose, lactate, pyruvate, and a fatty acid (palmitate, oleate or docosanoate). In each experiment, substrates were13C-labeled to yield singly or/and doubly labeled acetyl-CoA. The mass isotopomer distribution of malonyl-CoA was compared with that of the acetyl moiety of citrate, which reflects mitochondrial acetyl-CoA. In the presence of labeled glucose or lactate/pyruvate, the13C labeling of malonyl-CoA was up to 2-fold lower than that of mitochondrial acetyl-CoA. However, in the presence of a fatty acid labeled in its first acetyl moiety, the13C labeling of malonyl-CoA was up to 10-fold higher than that of mitochondrial acetyl-CoA. The labeling of malonyl-CoA and of the acetyl moiety of citrate is compatible with peroxisomal β-oxidation forming C12and C14acyl-CoAs and contributing >50% of the fatty acid-derived acetyl groups that end up in malonyl-CoA. This fraction increases with the fatty acid chain length. By supplying acetyl-CoA for malonyl-CoA synthesis, peroxisomal β-oxidation may participate in the control of mitochondrial fatty acid oxidation in the heart. In addition, this pathway may supply some acyl groups used in protein acylation, which is increasingly recognized as an important regulatory mechanism for many biochemical processes.

scholarly journals Peroxisomal oxidation of erucic acid suppresses mitochondrial fatty acid oxidation by stimulating malonyl-CoA formation in the rat liver

2020 ◽  
Vol 295 (30) ◽  
pp. 10168-10179 ◽  
Author(s):  
Xiaocui Chen ◽  
Lin Shang ◽  
Senwen Deng ◽  
Ping Li ◽  
Kai Chen ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Erucic Acid ◽  
Hepatic Steatosis ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Acetyl Coa ◽  
Mitochondrial Fatty Acid Oxidation ◽  
High Erucic Acid ◽  
Malonyl Coa ◽  
Mitochondrial Fatty Acid

Feeding of rapeseed (canola) oil with a high erucic acid concentration is known to cause hepatic steatosis in animals. Mitochondrial fatty acid oxidation plays a central role in liver lipid homeostasis, so it is possible that hepatic metabolism of erucic acid might decrease mitochondrial fatty acid oxidation. However, the precise mechanistic relationship between erucic acid levels and mitochondrial fatty acid oxidation is unclear. Using male Sprague–Dawley rats, along with biochemical and molecular biology approaches, we report here that peroxisomal β-oxidation of erucic acid stimulates malonyl-CoA formation in the liver and thereby suppresses mitochondrial fatty acid oxidation. Excessive hepatic uptake and peroxisomal β-oxidation of erucic acid resulted in appreciable peroxisomal release of free acetate, which was then used in the synthesis of cytosolic acetyl-CoA. Peroxisomal metabolism of erucic acid also remarkably increased the cytosolic NADH/NAD+ ratio, suppressed sirtuin 1 (SIRT1) activity, and thereby activated acetyl-CoA carboxylase, which stimulated malonyl-CoA biosynthesis from acetyl-CoA. Chronic feeding of a diet including high-erucic-acid rapeseed oil diminished mitochondrial fatty acid oxidation and caused hepatic steatosis and insulin resistance in the rats. Of note, administration of a specific peroxisomal β-oxidation inhibitor attenuated these effects. Our findings establish a cross-talk between peroxisomal and mitochondrial fatty acid oxidation. They suggest that peroxisomal oxidation of long-chain fatty acids suppresses mitochondrial fatty acid oxidation by stimulating malonyl-CoA formation, which might play a role in fatty acid–induced hepatic steatosis and related metabolic disorders.

scholarly journals Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

2016 ◽  
Vol 311 (2) ◽  
pp. H347-H363 ◽  
Author(s):  
Arata Fukushima ◽  
Osama Abo Alrob ◽  
Liyan Zhang ◽  
Cory S. Wagg ◽  
Tariq Altamimi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Metabolism ◽  
Fatty Acid Oxidation ◽  
Glucose Oxidation ◽  
Acid Oxidation ◽  
Amino Acid Synthesis ◽  
Oxidation Rates ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy ◽  
The Impact

Dramatic maturational changes in cardiac energy metabolism occur in the newborn period, with a shift from glycolysis to fatty acid oxidation. Acetylation and succinylation of lysyl residues are novel posttranslational modifications involved in the control of cardiac energy metabolism. We investigated the impact of changes in protein acetylation/succinylation on the maturational changes in energy metabolism of 1-, 7-, and 21-day-old rabbit hearts. Cardiac fatty acid β-oxidation rates increased in 21-day vs. 1- and 7-day-old hearts, whereas glycolysis and glucose oxidation rates decreased in 21-day-old hearts. The fatty acid oxidation enzymes, long-chain acyl-CoA dehydrogenase (LCAD) and β-hydroxyacyl-CoA dehydrogenase (β-HAD), were hyperacetylated with maturation, positively correlated with their activities and fatty acid β-oxidation rates. This alteration was associated with increased expression of the mitochondrial acetyltransferase, general control of amino acid synthesis 5 like 1 (GCN5L1), since silencing GCN5L1 mRNA in H9c2 cells significantly reduced acetylation and activity of LCAD and β-HAD. An increase in mitochondrial ATP production rates with maturation was associated with the decreased acetylation of peroxisome proliferator-activated receptor-γ coactivator-1α, a transcriptional regulator for mitochondrial biogenesis. In addition, hypoxia-inducible factor-1α, hexokinase, and phosphoglycerate mutase expression declined postbirth, whereas acetylation of these glycolytic enzymes increased. Phosphorylation rather than acetylation of pyruvate dehydrogenase (PDH) increased in 21-day-old hearts, accounting for the low glucose oxidation postbirth. A maturational increase was also observed in succinylation of PDH and LCAD. Collectively, our data are the first suggesting that acetylation and succinylation of the key metabolic enzymes in newborn hearts play a crucial role in cardiac energy metabolism with maturation. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/acetylation-control-of-energy-metabolism-in-newborn-hearts/ .

Effect of phosphorylation by AMP-activated protein kinase on palmitoyl-CoA inhibition of skeletal muscle acetyl-CoA carboxylase

2005 ◽  
Vol 98 (4) ◽  
pp. 1221-1227 ◽  
Author(s):  
D. S. Rubink ◽  
W. W. Winder
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Oxidation Rates ◽  
Malonyl Coa ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) has previously been demonstrated to phosphorylate and inactivate skeletal muscle acetyl-CoA carboxylase (ACC), the enzyme responsible for synthesis of malonyl-CoA, an inhibitor of carnitine palmitoyltransferase 1 and fatty acid oxidation. Contraction-induced activation of AMPK with subsequent phosphorylation/inactivation of ACC has been postulated to be responsible in part for the increase in fatty acid oxidation that occurs in muscle during exercise. These studies were designed to answer the question: Does phosphorylation of ACC by AMPK make palmitoyl-CoA a more effective inhibitor of ACC? Purified rat muscle ACC was subjected to phosphorylation by AMPK. Activity was determined on nonphosphorylated and phosphorylated ACC preparations at acetyl-CoA concentrations ranging from 2 to 500 μM and at palmitoyl-CoA concentrations ranging from 0 to 100 μM. Phosphorylation resulted in a significant decline in the substrate saturation curve at all palmitoyl-CoA concentrations. The inhibitor constant for palmitoyl-CoA inhibition of ACC was reduced from 1.7 ± 0.25 to 0.85 ± 0.13 μM as a consequence of phosphorylation. At 0.5 mM citrate, ACC activity was reduced to 13% of control values in response to the combination of phosphorylation and 10 μM palmitoyl-CoA. Skeletal muscle ACC is more potently inhibited by palmitoyl-CoA after having been phosphorylated by AMPK. This may contribute to low-muscle malonyl-CoA values and increasing fatty acid oxidation rates during long-term exercise when plasma fatty acid concentrations are elevated.

scholarly journals Metabolic Therapy in Heart Failure

2015 ◽  
Vol 1 (2) ◽  
pp. 112 ◽  
Author(s):  
Yury Lopatin ◽  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Glucose Oxidation ◽  
Acid Oxidation ◽  
Patients With Heart Failure ◽  
Cardiac Energy Metabolism ◽  
Conventional Medical Therapy ◽  
Cardiac Energy ◽  
Metabolic Impairments

Metabolic impairments play an important role in the development and progression of heart failure. The use of metabolic modulators, the number of which is steadily increasing, may be particularly effective in the treatment of heart failure. Recent evidence suggests that modulating cardiac energy metabolism by reducing fatty acid oxidation and/or increasing glucose oxidation represents a promising approach to the treatment of patients with heart failure. This review focuses on the role of metabolic modulators, in particular trimetazidine, as a potential additional medication to conventional medical therapy in heart failure.

Abstract 15649: Pharmacological Inhibition of Aldose Reductase by AT001 Prevents Abnormal Cardiac Energy Metabolism and Improves Heart Function in an Animal Model of Diabetic Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Keshav Gopal ◽  
Qutuba Karwi ◽  
Seyed Amirhossein Tabatabaei Dakhili ◽  
Riccardo Perfetti ◽  
Ravichandran Ramasamy ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Energy Metabolism ◽  
Fatty Acid Oxidation ◽  
Diabetic Cardiomyopathy ◽  
Acid Oxidation ◽  
Cardiac Energetics ◽  
Cardiac Efficiency ◽  
Oxidation Rates ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

Introduction: Diabetic Cardiomyopathy (DCM) is a major cause of death in people with type 2 diabetes (T2D). Alterations in cardiac energy metabolism including increased fatty acid oxidation rates and reduced glucose oxidation rates are key contributing factors to the development of DCM. Studies have shown that Aldose Reductase (AR), an enzyme activated under hyperglycemic conditions, can modulate myocardial glucose and fatty acid oxidation, and promotes cardiac dysfunction. Hypothesis: Pharmacological inhibition of AR using a next-generation inhibitor AT-001, can mitigate DCM in mice by modulating cardiac energy metabolism and improving cardiac efficiency. Methods: Male human AR overexpressing (hAR-Tg) and C57BL/6J (Control) mice were subjected to experimental T2D (high-fat diet [60% kcal from lard] for 10-wk with a single intraperitoneal streptozotocin injection of 75 mg/kg) and treated for the last 3-wk with AT-001 (40mg/kg/day) or vehicle via oral gavage. Cardiac energy metabolism and in vivo cardiac function were assessed via isolated working heart perfusions and ultrasound echocardiography, respectively. Results: AT-001 treatment significantly improved cardiac energetics in a murine model of DCM (hAR-Tg mice with T2D). Particularly, AT-001-treated mice exhibited decreased cardiac fatty acid oxidation rates compared to the vehicle-treated mice (342 ± 53 vs 964 ± 130 nmol/min/g dry wt.). Concurrently, there was a significant decrease in cardiac oxygen consumption in the AT-001-treated compared to the vehicle-treated mice (41 ± 12 vs 60 ± 11 μmol/min/g dry wt.), suggesting increased cardiac efficiency. Furthermore, treatment with AT-001 prevented cardiac structural and functional abnormalities present in DCM, including diastolic dysfunction as reflected by an increase in the tissue Doppler E’/A’ ratio and decrease in E/E’ ratio. Moreover, AT-001 treatment prevented cardiac hypertrophy as reflected by a decrease in LV mass in AT-001-treated mice. Conclusions: AR inhibition with AT-001 prevents cardiac structural and functional abnormalities in a mouse model of DCM, and normalizes cardiac energetics by shifting cardiac metabolism towards a non-diabetic metabolic state.

Regulation of myocardial fatty acid oxidation by substrate supply

2001 ◽  
Vol 281 (4) ◽  
pp. H1561-H1567 ◽  
Author(s):  
Sarah L. Longnus ◽  
Richard B. Wambolt ◽  
Rick L. Barr ◽  
Gary D. Lopaschuk ◽  
Michael F. Allard
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Acetyl Coa ◽  
Regulatory Pathways ◽  
Oxidation Rates ◽  
Substrate Supply ◽  
Exogenous Substrate ◽  
Malonyl Coa ◽  
Myocardial Substrate

We tested the hypothesis that myocardial substrate supply regulates fatty acid oxidation independent of changes in acetyl-CoA carboxylase (ACC) and 5′-AMP-activated protein kinase (AMPK) activities. Fatty acid oxidation was measured in isolated working rat hearts exposed to different concentrations of exogenous long-chain (0.4 or 1.2 mM palmitate) or medium-chain (0.6 or 2.4 mM octanoate) fatty acids. Fatty acid oxidation was increased with increasing exogenous substrate concentration in both palmitate and octanoate groups. Malonyl-CoA content only rose as acetyl-CoA supply from octanoate oxidation increased. The increases in octanoate oxidation and malonyl-CoA content were independent of changes in ACC and AMPK activity, except that ACC activity increased with very high acetyl-CoA supply levels. Our data suggest that myocardial substrate supply is the primary mechanism responsible for alterations in fatty acid oxidation rates under nonstressful conditions and when substrates are present at physiological concentrations. More extreme variations in substrate supply lead to changes in fatty acid oxidation by the additional involvement of intracellular regulatory pathways.

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