Cytosolic carnitine acetyltransferase as a source of cytosolic acetyl-CoA: a possible mechanism for regulation of cardiac energy metabolism

2018 ◽  
Vol 475 (5) ◽  
pp. 959-976 ◽  
Author(s):  
Tariq R. Altamimi ◽  
Panakkezhum D. Thomas ◽  
Ahmed M. Darwesh ◽  
Natasha Fillmore ◽  
Mohammad U. Mahmoud ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Glucose Oxidation ◽  
Carnitine Acetyltransferase ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Protein Levels ◽  
Citrate Lyase ◽  
Malonyl Coa ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

The role of carnitine acetyltransferase (CrAT) in regulating cardiac energy metabolism is poorly understood. CrAT modulates mitochondrial acetyl-CoA/CoA (coenzyme A) ratios, thus regulating pyruvate dehydrogenase activity and glucose oxidation. Here, we propose that cardiac CrAT also provides cytosolic acetyl-CoA for the production of malonyl-CoA, a potent inhibitor of fatty acid oxidation. We show that in the murine cardiomyocyte cytosol, reverse CrAT activity (RCrAT, producing acetyl-CoA) is higher compared with the liver, which primarily uses ATP-citrate lyase to produce cytosolic acetyl-CoA for lipogenesis. The heart displayed a lower RCrAT Km for CoA compared with the liver. Furthermore, cytosolic RCrAT accounted for 4.6 ± 0.7% of total activity in heart tissue and 12.7 ± 0.2% in H9C2 cells, while highly purified heart cytosolic fractions showed significant CrAT protein levels. To investigate the relationship between CrAT and acetyl-CoA carboxylase (ACC), the cytosolic enzyme catalyzing malonyl-CoA production from acetyl-CoA, we studied ACC2-knockout mouse hearts which showed decreased CrAT protein levels and activity, associated with increased palmitate oxidation and acetyl-CoA/CoA ratio compared with controls. Conversely, feeding mice a high-fat diet for 10 weeks increased cardiac CrAT protein levels and activity, associated with a reduced acetyl-CoA/CoA ratio and glucose oxidation. These data support the presence of a cytosolic CrAT with a low Km for CoA, favoring the formation of cytosolic acetyl-CoA, providing an additional source to the classical ATP-citrate lyase pathway, and that there is an inverse relation between CrAT and the ratio of acetyl-CoA/CoA as evident in conditions affecting the regulation of cardiac energy metabolism.

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/ .

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 (-)-Hydroxycitric Acid Reduced Lipid Droplets Accumulation Via Decreasing Acetyl-Coa Supply and Accelerating Energy Metabolism in Cultured Primary Chicken Hepatocytes

2017 ◽  
Vol 43 (2) ◽  
pp. 812-831 ◽  
Author(s):  
Longlong Li ◽  
Mengling Peng ◽  
Chongyang Ge ◽  
Lei Yu ◽  
Haitian Ma
Keyword(s):  
Energy Metabolism ◽  
Lipid Droplets ◽  
Fatty Acid Synthase ◽  
Mrna Level ◽  
Mrna Levels ◽  
Biochemical Mechanism ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Hydroxycitric Acid ◽  
Citrate Lyase

Background/Aims: (-)-Hydroxycitric acid (HCA) had been shown to suppress fat accumulation in animals and humans, while the underlying biochemical mechanism is not fully understood, especially little information is available on whether (-)-HCA regulates energy metabolism and consequently affects fat deposition. Methods: Hepatocytes were cultured for 24 h and then exposed to (-)-HCA (0, 1, 10, 50 µM), enzyme protein content was determined by ELISA; lipid metabolism gene mRNA levels were detected by RT-PCR. Results: (-)-HCA significantly decreased the number and total area of lipid droplets. ATP-citrate lyase, fatty acid synthase and sterol regulatory element binding protein-1c mRNA level were significantly decreased after (-)-HCA treatment, whereas peroxisome proliferator-activated receptor α mRNA level was significantly increased. (-)-HCA significantly decreased ATP-citrate lyase activity and acetyl-CoA content in cytosol, but significantly increased glucose consumption and mitochondrial oxygen consumption rate. (-)-HCA promoted the activity/content of glucokinase, phosphofructokinase-1, pyruvate kinase, pyruvate dehydrogenase, citrate synthase, aconitase, succinate dehydrogenase, malate dehydrogenase, NADH dehydrogenase and ATP synthase remarkably. Conclusions: (-)-HCA decreased lipid droplets accumulation by reducing acetyl-CoA supply, which mainly achieved via inhibition of ATP-citrate lyase, and accelerating energy metabolism in chicken hepatocytes. These results proposed a biochemical mechanism of fat reduction by (-)-HCA in broiler chickens in term of energy metabolism.

Probing the link between citrate and malonyl-CoA in perfused rat hearts

2002 ◽  
Vol 283 (4) ◽  
pp. H1379-H1386 ◽  
Author(s):  
Myriame Poirier ◽  
Geneviève Vincent ◽  
Aneta E. Reszko ◽  
Bertrand Bouchard ◽  
Joanne K. Kelleher ◽  
...  
Keyword(s):  
Carbon Sources ◽  
Acid Oxidation ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Rat Hearts ◽  
Citrate Lyase ◽  
Malonyl Coa ◽  
Perfused Rat Hearts ◽  
Citrate Release

Little is known about the sources of cytosolic acetyl-CoA used for the synthesis of malonyl-CoA, a key regulator of fatty acid oxidation in the heart. We tested the hypothesis that citrate provides acetyl-CoA for malonyl-CoA synthesis after its mitochondrial efflux and cleavage by cytosolic ATP-citrate lyase. We expanded on a previous study where we characterized citrate release from perfused rat hearts (Vincent G, Comte B, Poirier M, and Des Rosiers C. Citrate release by perfused rat hearts: a window on mitochondrial cataplerosis. Am J Physiol Endocrinol Metab 278: E846–E856, 2000). In the present study, we show that citrate release rates, ranging from 6 to 22 nmol/min, can support a net increase in malonyl-CoA concentrations induced by changes in substrate supply, at most 0.7 nmol/min. In experiments with [U-13C](lactate + pyruvate) and [1-13C]oleate, we show that the acetyl moiety of malonyl-CoA is derived from both pyruvate and long-chain fatty acids. This 13C-labeling of malonyl-CoA occurred without any changes in its concentration. Hydroxycitrate, an inhibitor of ATP-citrate lyase, prevents increases in malonyl-CoA concentrations and decreases its labeling from [U-13C](lactate + pyruvate). Our data support at least a partial role of citrate in the transfer from the mitochondria to cytosol of acetyl units for malonyl-CoA synthesis. In addition, they provide a dynamic picture of malonyl-CoA metabolism: even when the malonyl-CoA concentration remains constant, there appears to be a constant need to supply acetyl-CoA from various carbon sources, both carbohydrates and lipids, for malonyl-CoA synthesis.

PPARα regulates cardiac energy metabolism by controlling malonyl COA concentrations in the heart

2001 ◽  
Vol 33 (6) ◽  
pp. A164
Author(s):  
Fiona M. Campbell ◽  
Ray Kozak ◽  
Alese Wagner ◽  
Judith Y. Altarelos ◽  
Jason R.B. Dyck ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Malonyl Coa ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

Malonyl-CoA regulation in skeletal muscle: its link to cell citrate and the glucose-fatty acid cycle

1997 ◽  
Vol 272 (4) ◽  
pp. E641-E648 ◽  
Author(s):  
A. K. Saha ◽  
D. Vavvas ◽  
T. G. Kurowski ◽  
A. Apazidis ◽  
L. A. Witters ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Pancreatic Beta Cell ◽  
Acid Oxidation ◽  
Atp Citrate Lyase ◽  
Acetyl Coa ◽  
Acid Cycle ◽  
Citrate Lyase ◽  
Malonyl Coa ◽  
Glucose Fatty Acid Cycle

Malonyl-CoA is an inhibitor of carnitine palmitoyltransferase I, the enzyme that controls the oxidation of fatty acids by regulating their transfer into the mitochondria. Despite this, knowledge of how malonyl-CoA levels are regulated in skeletal muscle, the major site of fatty acid oxidation, is limited. Two- to fivefold increases in malonyl-CoA occur in rat soleus muscles incubated with glucose or glucose plus insulin for 20 min [Saha, A. K., T. G. Kurowski, and N. B. Ruderman. Am. J. Physiol. 269 (Endocrinol. Metab. 32): E283-E289, 1995]. In addition, as reported here, acetoacetate in the presence of glucose increases malonyl-CoA levels in the incubated soleus. The increases in malonyl-CoA in all of these situations correlated closely with increases in the concentration of citrate (r2 = 0.64) and to an even greater extent the sum of citrate plus malate (r2 = 0.90), an antiporter for citrate efflux from the mitochondria. Where measured, no increase in the activity of acetyl-CoA carboxylase (ACC) was found. Inhibition of ATP citrate lyase with hydroxycitrate markedly diminished the increases in malonyl-CoA in these muscles, indicating that citrate was the major substrate for the malonyl-CoA precursor, cytosolic acetyl-CoA. Studies with enzyme purified by immunoprecipitation indicated that the observed increases in citrate could have also allosterically activated ACC. The results suggest that in the presence of glucose, insulin and acetoacetate acutely increase malonyl-CoA levels in the incubated soleus by increasing the cytosolic concentration of citrate. This novel mechanism could complement the glucose-fatty acid cycle in determining how muscle chooses its fuels. It could also provide a means by which glucose acutely modulates signal transduction in muscle and other cells (e.g., the pancreatic beta-cell) in which its metabolism is determined by substrate availability.

scholarly journals A Role for ATP-Citrate Lyase, Malic Enzyme, and Pyruvate/Citrate Cycling in Glucose-induced Insulin Secretion

2007 ◽  
Vol 282 (49) ◽  
pp. 35657-35665 ◽  
Author(s):  
Claudiane Guay ◽  
S. R. Murthy Madiraju ◽  
Alexandre Aumais ◽  
Érik Joly ◽  
Marc Prentki
Keyword(s):  
Insulin Secretion ◽  
Malic Enzyme ◽  
Acid Oxidation ◽  
Atp Citrate Lyase ◽  
Protein Levels ◽  
Metabolic Coupling ◽  
Rnai Technology ◽  
Citrate Lyase ◽  
Malonyl Coa ◽  
Coupling Factors

In pancreatic β-cells, metabolic coupling factors generated during glucose metabolism and pyruvate cycling through anaplerosis/cataplerosis processes contribute to the regulation of insulin secretion. Pyruvate/citrate cycling across the mitochondrial membrane leads to the production of malonyl-CoA and NADPH, two candidate coupling factors. To examine the implication of pyruvate/citrate cycling in glucose-induced insulin secretion (GIIS), different steps of the cycle were inhibited in INS 832/13 cells by pharmacological inhibitors and/or RNA interference (RNAi) technology: mitochondrial citrate export, ATP-citrate lyase (ACL), and cytosolic malic enzyme (ME1). The inhibitors of the di- and tri-carboxylate carriers, n-butylmalonate and 1,2,3-benzenetricarboxylate, respectively, reduced GIIS, indicating the importance of transmitochondrial transport of tri- and dicarboxylates in the action of glucose. To directly test the role of ACL and ME1 in GIIS, small hairpin RNA (shRNA) were used to selectively decrease ACL or ME1 expression in transfected INS 832/13 cells. shRNA-ACL reduced ACL protein levels by 67%, and this was accompanied by a reduction in GIIS. The amplification/KATP-independent pathway of GIIS was affected by RNAi knockdown of ACL. The ACL inhibitor radicicol also curtailed GIIS. shRNA-ME1 reduced ME1 activity by 62% and decreased GIIS. RNAi suppression of either ACL or ME1 did not affect glucose oxidation. However, because ACL is required for malonyl-CoA formation, inhibition of ACL expression by shRNA-ACL decreased glucose incorporation into palmitate and increased fatty acid oxidation in INS 832/13 cells. Taken together, the results underscore the importance of pyruvate/citrate cycling in pancreatic β-cell metabolic signaling and the regulation of GIIS.

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