scholarly journals Inhibition by acetyl-CoA of hepatic carnitine acyltransferase and fatty acid oxidation

1983 ◽  
Vol 216 (2) ◽  
pp. 499-502 ◽  
Author(s):  
K McCormick ◽  
V J Notar-Francesco ◽  
K Sriwatanakul
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Acetyl Coa ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Acyltransferase Activity ◽  
Carnitine Acyltransferase ◽  
Mitochondrial Transfer ◽  
Mitochondrial Fatty Acid ◽  
Chain Acyl

At micromolar concentrations, acetyl-CoA inhibited hepatic carnitine acyltransferase activity and mitochondrial fatty acid oxidation. The inhibitory effects were not nearly as potent on a molar basis as those of malonyl-CoA; nevertheless, the cytosolic concentrations of acetyl-CoA, as yet unknown, may be sufficient (greater than 30 microM) to curtail appreciably the mitochondrial transfer of long-chain acyl-CoA units and fatty acid oxidation. Hence acetyl-CoA may also partially regulate hepatic ketogenesis.

Medium- and Short-Chain L-3-Hydroxyl-Acetyl-Coenzyme A Deficiency: A New Identified Mutation in Four Cases

2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S9-S9
Author(s):  
Sheng Feng ◽  
Deborah Cooper ◽  
Lu Tan ◽  
Gail Meyers ◽  
Michael Bennett
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Coenzyme A ◽  
Short Chain ◽  
Acid Oxidation ◽  
Sequencing Analysis ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Chain Acyl ◽  
Unusual Phenotype

Abstract Medium- and short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase (M/SCHAD, SCHAD) deficiency is a mitochondrial fatty acid oxidation disorder (FAOD). This enzyme catalyzes the penultimate step in fatty acid oxidation, the NAD+ dependent conversion of L-3-hydroxyacyl-CoA to 3-ketoacyl-CoA for medium- and short-chain acyl-CoA intermediates (C4-C12). The clinical presentations of most patients are recurrent hypoglycemia associated with hyperinsulinism. We presented four infants with C4 acyl-carnitine elevation identified by newborn screening that also showed an unusual phenotype of congenital hypotonia and gross developmental delay. Enzymatic studies confirmed the disease. Sequencing analysis of all the HADH coding exons on the four patients revealed a homozygous variant of a novel change (c.908G>T, p.Gly303Val). Western blot analysis subsequently confirmed the lack of the SCHAD protein. In addition, there is another previously reported benign variant (c.257T>C) identified in three infants. Therefore, we postulate that the HADH variant (c.908G>T) is indeed pathogenic and associated with a severe phenotype as evidenced by the cases described herein. Population screening for the c.908G>T mutation suggests this mutation to be common among Puerto Ricans. We recommend that SCHAD deficiency is included as part of the differential diagnosis of all infants with congenital hypotonia.

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 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.

scholarly journals Changes in the activities of the enzymes of hepatic fatty acid oxidation during development of the rat

1976 ◽  
Vol 154 (1) ◽  
pp. 49-56 ◽  
Author(s):  
P C Foster ◽  
E Bailey
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Outer Mitochondrial Membrane ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Carnitine Acyltransferase ◽  
Mitochondrial Fatty Acid ◽  
Foetal Life ◽  
Hydroxyacyl Coa Dehydrogenase ◽  
Hepatic Fatty Acid Oxidation

1. Changes in the activities of several enzymes involved in mitochondrial fatty acid oxidation were measured in livers of developing rats between late foetal life and maturity. The enzymes studied are medium- and long-chain ATP-dependent acyl-CoA synthetases of the outer mitochondrial membrane and matrix, GTP-dependent acyl-CoA synthetase, carnitine acyltransferase, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, general 3-oxoacyl-CoA thiolase and acetoacetyl-CoA thiolase.

scholarly journals l-carnitine acyltransferase in intact peroxisomes is inhibited by malonyl-CoA

1989 ◽  
Vol 262 (3) ◽  
pp. 801-806 ◽  
Author(s):  
J P Derrick ◽  
R R Ramsay
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Marker Enzyme ◽  
Mitochondrial Enzyme ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Peroxisomal Enzyme ◽  
Carnitine Acyltransferase ◽  
Malonyl Coa ◽  
Mitochondrial Fatty Acid

Inhibition of the overt mitochondrial carnitine palmitoyltransferase by malonyl-CoA is important in the regulation of fatty acid oxidation. In the past, the contribution of peroxisomal carnitine acyltransferase activity to the generation of medium- and long-chain acylcarnitines in the cytoplasm has been ignored. On the basis of marker enzyme levels, we now estimate that peroxisomal palmitoyltransferase activity constitutes about 20% of the peroxisomal plus overt-mitochondrial pool in fed rat liver. When assayed in situ, both the palmitoyltransferase and decanoyltransferase activities of gradient-purified peroxisomes are sensitive to malonyl-CoA, with up to 90% inhibition reached at less than 10 microM-malonyl-CoA. Very similar results were obtained with intact gradient-purified mitochondria from the same livers. In addition, the acyl-CoA substrate chain-length specificity was identical in both the peroxisomes and the mitochondria, with a decanoyltransferase/palmitoyltransferase ratio of 2. Thus the overt carnitine acyltransferase activities in peroxisomes and mitochondria have the same properties. Further, the malonyl-CoA sensitivity of the peroxisomal activity is lost on solubilization, as has been observed for the overt mitochondrial enzyme. It is suggested that malonyl-CoA inhibition of the peroxisomal enzyme as well as of the mitochondrial enzyme is important for the regulation of mitochondrial fatty acid oxidation.

Glucocorticoids promote mitochondrial fatty acid oxidation in the fetal heart

2019 ◽  
Author(s):  
Helena Urquijo ◽  
Emma N Panting ◽  
Roderick N Carter ◽  
Emma J Agnew ◽  
Caitlin S Wyrwoll ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fetal Heart ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Mitochondrial Fatty Acid
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