scholarly journals GPER-dependent estrogen signaling increases cardiac GCN5L1 expression and MCAD activity

2021 ◽  
Author(s):  
Janet R Manning ◽  
Dharendra Thapa ◽  
Manling Zhang ◽  
Michael W Stoner ◽  
John C Sembrat ◽  
...  
Keyword(s):  
Contractile Activity ◽  
Cardiac Cells ◽  
Estrogen Signaling ◽  
Acid Oxidation ◽  
Mitochondrial Enzymes ◽  
Lysine Acetylation ◽  
Oxidation Rates ◽  
Acetylation Status ◽  
Chain Acyl ◽  
Fatty Acid Oxidation Enzyme

Reversible lysine acetylation regulates the activity of cardiac metabolic enzymes, including those controlling fuel substrate metabolism. Mitochondrial-targeted GCN5L1 and SIRT3 have been shown to regulate the acetylation status of mitochondrial enzymes, which results in alterations to the relative oxidation rates of fatty acids, glucose, and other fuels for contractile activity. However, the role that lysine acetylation plays in driving metabolic differences between male and female hearts is not currently known. In this study, we report that estrogens induce the expression of GCN5L1 via GPER agonism in cardiac cells, which increases the enzymatic activity and acetylation status of the fatty acid oxidation enzyme medium chain acyl-CoA dehydrogenase (MCAD).

scholarly journals Acetylation of mitochondrial proteins by GCN5L1 promotes enhanced fatty acid oxidation in the heart

2017 ◽  
Vol 313 (2) ◽  
pp. H265-H274 ◽  
Author(s):  
Dharendra Thapa ◽  
Manling Zhang ◽  
Janet R. Manning ◽  
Danielle A. Guimarães ◽  
Michael W. Stoner ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
High Fat Diet ◽  
Acid Oxidation ◽  
Lysine Acetylation ◽  
High Fat ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Acetylation Status ◽  
Mitochondrial Fatty Acid ◽  
Chain Acyl

Lysine acetylation is a reversible posttranslational modification and is particularly important in the regulation of mitochondrial metabolic enzymes. Acetylation uses acetyl-CoA derived from fuel metabolism as a cofactor, thereby linking nutrition to metabolic activity. In the present study, we investigated how mitochondrial acetylation status in the heart is controlled by food intake and how these changes affect mitochondrial metabolism. We found that there was a significant increase in cardiac mitochondrial protein acetylation in mice fed a long-term high-fat diet and that this change correlated with an increase in the abundance of the mitochondrial acetyltransferase-related protein GCN5L1. We showed that the acetylation status of several mitochondrial fatty acid oxidation enzymes (long-chain acyl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase, and hydroxyacyl-CoA dehydrogenase) and a pyruvate oxidation enzyme (pyruvate dehydrogenase) was significantly upregulated in high-fat diet-fed mice and that the increase in long-chain and short-chain acyl-CoA dehydrogenase acetylation correlated with increased enzymatic activity. Finally, we demonstrated that the acetylation of mitochondrial fatty acid oxidation proteins was decreased after GCN5L1 knockdown and that the reduced acetylation led to diminished fatty acid oxidation in cultured H9C2 cells. These data indicate that lysine acetylation promotes fatty acid oxidation in the heart and that this modification is regulated in part by the activity of GCN5L1. NEW & NOTEWORTHY Recent research has shown that acetylation of mitochondrial fatty acid oxidation enzymes has greatly contrasting effects on their activity in different tissues. Here, we provide new evidence that acetylation of cardiac mitochondrial fatty acid oxidation enzymes by GCN5L1 significantly upregulates their activity in diet-induced obese mice.

Effects of valproic acid on cardiac metabolism

2004 ◽  
Vol 82 (10) ◽  
pp. 927-933 ◽  
Author(s):  
Thomas Daniels ◽  
Maureen Gallagher ◽  
George Tremblay ◽  
Robert L Rodgers
Keyword(s):  
Valproic Acid ◽  
Fatty Acid ◽  
Cardiac Metabolism ◽  
Acid Oxidation ◽  
Oxidation Rates ◽  
Coa Ligase ◽  
Rat Hearts ◽  
Chain Acyl ◽  
Oxidation Of Glucose

We investigated whether the antiepileptic valproic acid (VPA) might interfere with oxidative metabolism in heart, as it does in liver. We administered VPA to working rat hearts perfused with radiolabeled carbohydrate and fatty acid fuels. Measurements included oxidation rates of (i) glucose, pyruvate, or lactate in the presence of palmitate and (ii) palmitate, octanoate, or butyrate in the presence of glucose. Oxidation rates were quantified as the rate of appearance of14CO2or3H2O from14C- or3H-labeled substrates. In hearts perfused with palmitate, VPA (1 mmol/L) strongly inhibited the oxidation of pyruvate and lactate but slightly stimulated the oxidation of glucose. VPA also inhibited lactate or pyruvate uptake into erythrocytes in vitro. In hearts perfused with glucose, VPA strongly inhibited the oxidation of palmitate and octanoate but had no effect on butyrate oxidation. The absence of valproate CoA ligase activity in cell-free homogenates indicated that the inhibition of fatty acid oxidation by VPA did not require prior activation to valproyl-CoA. The results are consistent with the hypothesis that VPA selectively interferes with myocardial fuel oxidation by mechanisms that are independent of conversion to the CoA thioester.Key words: myocardial, glucose, lactate, pyruvate, palmitate, octanoate, butyrate, metabolism, medium-chain acyl-CoA ligase.

379-P: Aldose Reductase Inhibition by AT-001 Prevents Diabetic Cardiomyopathy via Reducing Myocardial Fatty Acid Oxidation Rates

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 379-P
Author(s):  
KESHAV GOPAL ◽  
QUTUBA G. KARWI ◽  
SEYED AMIRHOSSEIN TABATABAEI DAKHILI ◽  
CORY S. WAGG ◽  
RICCARDO PERFETTI ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Aldose Reductase ◽  
Diabetic Cardiomyopathy ◽  
Acid Oxidation ◽  
Myocardial Fatty Acid ◽  
Aldose Reductase Inhibition ◽  
Oxidation Rates

Abstract 282: Adropin Enhancement of Cardiac Insulin Sensitivity and Inhibition of Fatty Acid Oxidation are Associated With Improvement of Cardiac Function and Efficiency in Hearts From Fasted Mice

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Tariq R Altamimi ◽  
Arata Fukushima ◽  
Liyan Zhang ◽  
Su Gao ◽  
Abhishek Gupta ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Diabetic Cardiomyopathy ◽  
Insulin Signaling ◽  
Plasma Levels ◽  
Acid Oxidation ◽  
Post Translational Modification ◽  
Cardiac Efficiency ◽  
Oxidation Rates ◽  
Cardiac Energy

Impaired cardiac insulin signaling and high cardiac fatty acid oxidation rates are characteristics of diabetic cardiomyopathy. Potential roles for liver-derived metabolic factors in mediating cardiac energy homeostasis are underappreciated. Plasma levels of adropin, a liver secreted peptide, increase during feeding and decrease during fasting and diabetes. In skeletal muscle, adropin preferentially promotes glucose over fatty acid oxidation. We therefore determined what effect adropin has on cardiac energy metabolism, insulin signaling and cardiac efficiency. C57Bl/6 mice were fasted to accentuate the differences in adropin plasma levels between animals injected 3 times over 24 hr with either vehicle or adropin (450 nmol/kg i.p.). Despite fasting-induced predominance of fatty acid oxidation measured in isolated working hearts, insulin inhibition of fatty acid oxidation was re-established in adropin-treated mice (from 1022±143 to 517±56 nmol. g dry wt -1 . min -1 , p <0.05) compared to vehicle-treated mice (from 757±104 to 818±103 nmol. g dry wt -1 . min -1 ). Adropin-treated mice hearts showed higher cardiac work over the course of perfusion (p<0.05 vs. vehicle), which was accompanied by improved cardiac efficiency and enhanced phosphorylation of insulin signaling enzymes (tyrosine-IRS-1, AS160, p<0.05). Acute addition of adropin (2nM) to isolated working hearts from non-fasting mice showed a robust stimulation of glucose oxidation compared to vehicle-treated hearts (3025±401 vs 1708±292 nmol. g dry wt -1 . min -1 , p<0.05, respectively) with a corresponding inhibition of palmitate oxidation (325±61 vs 731±160 nmol. g dry wt -1 . min -1 , p<0.05, respectively), even in the presence of insulin. Acute adropin addition to hearts also increased IRS-1 tyrosine-phosphorylation as well as Akt, and GSK3β phosphorylation (p<0.05), suggesting acute receptor- and/or post-translational modification-mediated mechanisms. These results suggest adropin as a putative candidate for the treatment of diabetic cardiomyopathy.

Interactions between sustained contractile activity and beta-adrenergic receptors in regulation of gene expression in skeletal muscles

1989 ◽  
Vol 256 (3) ◽  
pp. C506-C514 ◽  
Author(s):  
W. E. Kraus ◽  
T. S. Bernard ◽  
R. S. Williams
Keyword(s):  
Electrical Stimulation ◽  
Steady State ◽  
Oxidative Metabolism ◽  
Adrenergic Receptors ◽  
Contractile Activity ◽  
Mitochondrial Enzymes ◽  
Beta Adrenergic Receptors ◽  
Beta Adrenergic ◽  
Induced Changes ◽  
Aldolase A

Continuous electrical stimulation for 10-21 days of the motor nerve innervating the anterior compartment muscles of adult rabbits increased both the density of beta-adrenergic receptors (beta-AR) and tissue concentrations of adenosine 3',5'-cyclic monophosphate (cAMP) by two to threefold. Changes in cAMP and in beta-AR occurred in parallel with stimulation-induced adaptations in the specific activity of mitochondrial enzymes (2- to 6-fold increases) and with changes in steady-state concentrations of mitochondrial RNA, beta-F1ATPase mRNA, and myoglobin mRNA (2- to 11-fold increases). These increases in muscle cAMP, in beta-AR, and in expression of protein and mRNA products of genes encoding proteins of oxidative metabolism occurred even in animals receiving high doses of propranolol during the period of electrical stimulation. In contrast to genes that encode proteins of oxidative metabolism, the direction and the time course of activity-induced changes in expression of the glycolytic enzyme aldolase A appeared to be unrelated to changes in muscle cAMP; suppression of steady-state concentrations of aldolase A mRNA was maximal (20-25% of control) at early time points preceding the maximal rise in cAMP. In addition, administration of propranolol attenuated the suppressive effect of continuous contractile activity on expression of aldolase A, even in the absence of an effect of this drug on cAMP in stimulated muscles. We conclude that activity-induced changes in cAMP, in beta-AR, and in expression of genes that encode proteins important for oxidative metabolism occur as a direct consequence of contractile activity and do not require concomitant stimulation of beta-AR.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of 1 wk of diabetes on the regulation of myocardial carbohydrate and fatty acid oxidation

1999 ◽  
Vol 277 (2) ◽  
pp. E342-E351 ◽  
Author(s):  
John C. Chatham ◽  
Zhi-Ping Gao ◽  
John R. Forder
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fold Increase ◽  
Diabetic Rats ◽  
Diabetic Group ◽  
Acid Oxidation ◽  
Oxidation Rates ◽  
Tissue Extracts ◽  
Isotopomer Analysis ◽  
C Nmr

The aim of this study was to investigate the effect of increasing exogenous palmitate concentration on carbohydrate and palmitate oxidation in hearts from control and 1-wk diabetic rats. Hearts were perfused with glucose, [3-13C]lactate, and [U-13C]palmitate. Substrate oxidation rates were determined by combining13C-NMR glutamate isotopomer analysis of tissue extracts with measurements of oxygen consumption. Carbohydrate oxidation was markedly depressed after diabetes in the presence of low (0.1 mM) but not high (1.0 mM) palmitate concentration. Increasing exogenous palmitate concentration 10-fold resulted in a 7-fold increase in the contribution of palmitate to energy production in controls but only a 30% increase in the diabetic group. Consequently, at 0.1 mM palmitate, the rate of fatty acid oxidation was higher in the diabetic group than in controls; however, at 1.0 mM fatty acid oxidation, it was significantly depressed. Therefore, after 1 wk of diabetes, the major differences in carbohydrate and fatty acid metabolism occur primarily at low rather than high exogenous palmitate concentration.

Fatty acid metabolism in hearts containing elevated levels of CoA

1986 ◽  
Vol 250 (3) ◽  
pp. H351-H359 ◽  
Author(s):  
G. D. Lopaschuk ◽  
C. A. Hansen ◽  
J. R. Neely
Keyword(s):  
Fatty Acid ◽  
Specific Activity ◽  
Pantothenic Acid ◽  
Acid Oxidation ◽  
Palmitate Oxidation ◽  
Triacylglycerol Hydrolysis ◽  
Chain Acyl ◽  
Apparent Decrease ◽  
Apparent Reduction ◽  
14Co2 Production

Palmitate metabolism was determined in isolated perfused hearts containing elevated levels of coenzyme A (CoA). CoA levels were elevated by perfusing hearts with Krebs-Henseleit buffer containing 0.1 mM cysteine, 0.2 mM dithiothreitol, 15 microM pantothenic acid, and no energy substrate. After 45 min, CoA levels had increased from 537 +/- 14 to 818 +/- 44 nmol/g dry wt. When these hearts containing high CoA were subsequently perfused as working hearts with buffer containing 11 mM glucose and 1.2 mM palmitate, long chain acyl CoA levels increased (94 +/- 5-305 +/- 6 nmol/g dry wt). Oxidation of exogenous palmitate (as measured by 14CO2 production from [U-14C]palmitate) was significantly depressed in hearts containing elevated CoA levels. This apparent reduction in fatty acid oxidation was not due to increased glucose or glycogen utilization. When the concentration of palmitate was decreased to 0.4 mM, acyl CoA levels increased much less, and the apparent rate of [14C]palmitate oxidation was unaffected by elevated CoA. Hearts containing high CoA also incorporated [14C]palmitate into triacylglycerols to a greater extent than did control hearts. To determine whether the apparent decrease in exogenous palmitate oxidation resulted from an increased utilization of unlabeled endogenous triacylglycerol fatty acid, [14C]palmitate specific activity was measured in myocardial acylcarnitine. The specific activity of this pool of fatty acid was similar in both control hearts and hearts containing elevated CoA. Thus dilution of the total cellular [14C]acyl carnitine by triacylglycerol hydrolysis was not sufficient to account for the decrease in [U-14C]palmitate oxidation. The possibility that a small pool of rapidly turning over acyl carnitine becomes dilated is discussed.(ABSTRACT TRUNCATED AT 250 WORDS)

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/ .

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