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Cell Metabolism Jun 2022Elevated liver de novo lipogenesis contributes to non-alcoholic steatohepatitis (NASH) and can be inhibited by targeting acetyl-CoA carboxylase (ACC). However,...
Elevated liver de novo lipogenesis contributes to non-alcoholic steatohepatitis (NASH) and can be inhibited by targeting acetyl-CoA carboxylase (ACC). However, hypertriglyceridemia limits the use of pharmacological ACC inhibitors as a monotherapy. ATP-citrate lyase (ACLY) generates acetyl-CoA and oxaloacetate from citrate, but whether inhibition is effective for treating NASH is unknown. Here, we characterize a new mouse model that replicates many of the pathological and molecular drivers of NASH and find that genetically inhibiting ACLY in hepatocytes reduces liver malonyl-CoA, oxaloacetate, steatosis, and ballooning as well as blood glucose, triglycerides, and cholesterol. Pharmacological inhibition of ACLY mirrors genetic inhibition but has additional positive effects on hepatic stellate cells, liver inflammation, and fibrosis. Mendelian randomization of human variants that mimic reductions in ACLY also associate with lower circulating triglycerides and biomarkers of NASH. These data indicate that inhibiting liver ACLY may be an effective approach for treatment of NASH and dyslipidemia.
Topics: ATP Citrate (pro-S)-Lyase; Acetyl-CoA Carboxylase; Animals; Dyslipidemias; Liver; Liver Cirrhosis; Mice; Non-alcoholic Fatty Liver Disease; Oxaloacetates; Triglycerides
PubMed: 35675800
DOI: 10.1016/j.cmet.2022.05.004 -
Journal of Translational Medicine Jun 2022There is no approved pharmaceutical intervention for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS). Fatigue in these patients can last for decades. Long...
Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial.
BACKGROUND
There is no approved pharmaceutical intervention for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS). Fatigue in these patients can last for decades. Long COVID may continue to ME/CFS, and currently, it is estimated that up to 20 million Americans have significant symptoms after COVID, and the most common symptom is fatigue. Anhydrous Enol-Oxaloacetate, (AEO) a nutritional supplement, has been anecdotally reported to relieve physical and mental fatigue and is dimished in ME/CFS patients. Here, we examine the use of higher dosage AEO as a medical food to relieve pathological fatigue.
METHODS
ME/CFS and Long-COVID patients were enrolled in an open label dose escalating "Proof of Concept" non-randomized controlled clinical trial with 500 mg AEO capsules. Control was provided by a historical ME/CFS fatigue trial and supporting meta-analysis study, which showed average improvement with oral placebo using the Chalder Scale of 5.9% improvement from baseline. At baseline, 73.7% of the ME/CFS patients were women, average age was 47 and length of ME/CFS from diagnosis was 8.9 years. The Long-COVID patients were a random group that responded to social media advertising (Face Book) with symptoms for at least 6 months. ME/CFS patients were given separate doses of 500 mg BID (N = 23), 1,000 mg BID (N = 29) and 1000 mg TID (N = 24) AEO for six weeks. Long COVID patients were given 500 mg AEO BID (N = 22) and 1000 mg AEO (N = 21), again over a six-week period. The main outcome measure was to compare baseline scoring with results at 6 weeks with the Chalder Fatigue Score (Likert Scoring) versus historical placebo. The hypothesis being tested was formulated prior to data collection.
RESULTS
76 ME/CFS patients (73.7% women, median age of 47) showed an average reduction in fatigue at 6 weeks as measured by the "Chalder Fatigue Questionnaire" of 22.5% to 27.9% from baseline (P < 0.005) (Likert scoring). Both physical and mental fatigue were significantly improved over baseline and historical placebo. Fatigue amelioration in ME/CFS patients increased in a dose dependent manner from 21.7% for 500 mg BID to 27.6% for 1000 mg Oxaloacetate BID to 33.3% for 1000 mg TID. Long COVID patients' fatigue was significantly reduced by up to 46.8% in 6-weeks.
CONCLUSIONS
Significant reductions in physical and metal fatigue for ME/CFS and Long-COVID patients were seen after 6 weeks of treatment. As there has been little progress in providing fatigue relief for the millions of ME/CFS and Long COVID patients, anhydrous enol oxaloacetate may bridge this important medical need. Further study of oxaloacetate supplementation for the treatment of ME/CFS and Long COVID is warranted. Trial Registration https://clinicaltrials.gov/ct2/show/NCT04592354 Registered October 19, 2020. 1,000 mg BID Normalized Fatigue Data for Baseline, 2-weeks and 6-weeks evaluated by 3 Validated Fatigue Scoring Questionnaires.
Topics: COVID-19; Fatigue Syndrome, Chronic; Female; Humans; Male; Mental Fatigue; Middle Aged; Oxaloacetic Acid; Post-Acute COVID-19 Syndrome; COVID-19 Drug Treatment
PubMed: 35764955
DOI: 10.1186/s12967-022-03488-3 -
Nature Communications Jun 2023Accumulating evidence indicates that mitochondria play crucial roles in immunity. However, the role of the mitochondrial Krebs cycle in immunity remains largely unknown,...
Accumulating evidence indicates that mitochondria play crucial roles in immunity. However, the role of the mitochondrial Krebs cycle in immunity remains largely unknown, in particular at the organism level. Here we show that mitochondrial aconitase, ACO-2, a Krebs cycle enzyme that catalyzes the conversion of citrate to isocitrate, inhibits immunity against pathogenic bacteria in C. elegans. We find that the genetic inhibition of aco-2 decreases the level of oxaloacetate. This increases the mitochondrial unfolded protein response, subsequently upregulating the transcription factor ATFS-1, which contributes to enhanced immunity against pathogenic bacteria. We show that the genetic inhibition of mammalian ACO2 increases immunity against pathogenic bacteria by modulating the mitochondrial unfolded protein response and oxaloacetate levels in cultured cells. Because mitochondrial aconitase is highly conserved across phyla, a therapeutic strategy targeting ACO2 may eventually help properly control immunity in humans.
Topics: Humans; Animals; Aconitate Hydratase; Caenorhabditis elegans; Oxaloacetic Acid; Oxaloacetates; Unfolded Protein Response; Mammals
PubMed: 37349299
DOI: 10.1038/s41467-023-39393-6 -
Expert Review of Neurotherapeutics May 2015Pathologically elevated glutamate concentrations in the brain's extracellular fluid are associated with several acute and chronic brain insults. Studies have... (Review)
Review
Pathologically elevated glutamate concentrations in the brain's extracellular fluid are associated with several acute and chronic brain insults. Studies have demonstrated that by decreasing the concentration of glutamate in the blood, thereby increasing the concentration gradient between the brain and the blood, the rate of brain-to-blood glutamate efflux can be increased. Blood glutamate scavengers, pyruvate and oxaloacetate have shown great promise in providing neuroprotection in many animal models of acute brain insults. However, glutamate scavengers' potential systemic toxicity, side effects and pharmacokinetic properties may limit their use in clinical practice. In contrast, extracorporeal methods of blood glutamate reduction, in which glutamate is filtered from the blood and eliminated, may be an advantageous adjunct in treating acute brain insults. Here, we review the current evidence for the glutamate-lowering effects of hemodialysis, peritoneal dialysis and hemofiltration. The evidence reviewed here highlights the need for clinical trials.
Topics: Animals; Brain; Brain Diseases; Glutamic Acid; Humans; Neuroprotective Agents; Oxaloacetic Acid; Pyruvic Acid
PubMed: 25865745
DOI: 10.1586/14737175.2015.1032259 -
Frontiers in Endocrinology 2023This study aimed to identify preoperative blood biomarkers related to development of delayed neurocognitive recovery (dNCR) following surgery.
INTRODUCTION
This study aimed to identify preoperative blood biomarkers related to development of delayed neurocognitive recovery (dNCR) following surgery.
METHODS
A total of 67 patients (≥65 years old) who underwent head and neck tumor resection under general anesthesia were assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Preoperative serum metabolomics were determined using widely targeted metabolomics technology.
RESULTS
Of the 67 patients, 25 developed dNCR and were matched to 25 randomly selected patients from the remaining 42 without dNCR. Differential metabolites were selected using the criteria of variable importance in projection > 1.0 in orthogonal partial least squares discrimination analysis, false discovery rate <0.05, and fold-change >1.2 or <0.83 to minimize false positives. Preoperative serum levels of oxaloacetate (OR: 1.054, 95% CI: 1.027-1.095, = 0.001) and 2-aminoadipic acid (2-AAA) (OR: 1.181, 95% CI: 1.087-1.334, = 0.001) were associated with postoperative dNCR after adjusting for anesthesia duration, education, and age. Areas under the curve for oxaloacetate and 2-AAA were 0.86 (sensitivity: 0.84, specificity: 0.88) and 0.86 (sensitivity: 0.84, specificity: 0.84), respectively. High levels of preoperative oxaloacetate and 2-AAA also were associated with postoperative decreased MoCA (β: 0.022, 95% CI: 0.005-0.04, = 0.013 for oxaloacetate; β: 0.077, 95%CI: 0.016-0.137, = 0.014 for 2-AAA) and MMSE (β: 0.024, 95% CI: 0.009-0.039, = 0.002 for oxaloacetate; β: 0.083, 95% CI: 0.032-0.135, = 0.002 for 2-AAA) scores after adjusting for age, education level, and operation time.
CONCLUSION
High preoperative blood levels of oxaloacetate and 2-AAA were associated with increased risk of postoperative dNCR.
CLINICAL TRIAL REGISTRATION
https://classic.clinicaltrials.gov/ct2/show/NCT05105451, identifier NCT05105451.
Topics: Aged; Humans; 2-Aminoadipic Acid; Mental Status and Dementia Tests; Oxaloacetic Acid
PubMed: 37583434
DOI: 10.3389/fendo.2023.1212815 -
Alzheimer's & Dementia : the Journal of... Jan 2021Brain bioenergetics are defective in Alzheimer's disease (AD). Preclinical studies find oxaloacetate (OAA) enhances bioenergetics, but human safety and target engagement...
INTRODUCTION
Brain bioenergetics are defective in Alzheimer's disease (AD). Preclinical studies find oxaloacetate (OAA) enhances bioenergetics, but human safety and target engagement data are lacking.
METHODS
We orally administered 500 or 1000 mg OAA, twice daily for 1 month, to AD participants (n = 15 each group) and monitored safety and tolerability. To assess brain metabolism engagement, we performed fluorodeoxyglucose positron emission tomography (FDG PET) and magnetic resonance spectroscopy before and after the intervention. We also assessed pharmacokinetics and cognitive performance.
RESULTS
Both doses were safe and tolerated. Compared to the lower dose, the higher dose benefited FDG PET glucose uptake across multiple brain regions (P < .05), and the higher dose increased parietal and frontoparietal glutathione (P < .05). We did not demonstrate consistent blood level changes and cognitive scores did not improve.
CONCLUSIONS
1000 mg OAA, taken twice daily for 1 month, is safe in AD patients and engages brain energy metabolism.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cognition; Dose-Response Relationship, Drug; Energy Metabolism; Female; Fluorodeoxyglucose F18; Glucose; Glutathione; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Neuropsychological Tests; Oxaloacetic Acid; Positron-Emission Tomography; Radiopharmaceuticals
PubMed: 32715609
DOI: 10.1002/alz.12156 -
Scientific Reports May 2021Amyotrophic lateral sclerosis (ALS) remains a devastating motor neuron disease with limited treatment options. Oxaloacetate treatment has a neuroprotective effect in...
Amyotrophic lateral sclerosis (ALS) remains a devastating motor neuron disease with limited treatment options. Oxaloacetate treatment has a neuroprotective effect in rodent models of seizure and neurodegeneration. Therefore, we treated the ALS model superoxide dismutase 1 (SOD1) mice with oxaloacetate and evaluated their neuromuscular function and lifespan. Treatment with oxaloacetate beginning in the presymptomatic stage significantly improved neuromuscular strength measured during the symptomatic stage in the injected mice compared to the non-treated group. Oxaloacetate treatment starting in the symptomatic stage significantly delayed limb paralysis compared with the non-treated group. For lifespan analysis, oxaloacetate treatment did not show a statistically significant positive effect, but the treatment did not shorten the lifespan. Mechanistically, SOD1 mice showed increased levels of tumor necrosis factor-α (TNFα) and peroxisome proliferative activated receptor gamma coactivator 1α (PGC-1α) mRNAs in the spinal cord. However, oxaloacetate treatment reverted these abnormal levels to that of wild-type mice. Similarly, the altered expression level of total NF-κB protein returned to that of wild-type mice with oxaloacetate treatment. These results suggest that the beneficial effects of oxaloacetate treatment in SOD1 mice may reflect the effects on neuroinflammation or bioenergetic stress.
Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Inflammation; Longevity; Mice; Motor Activity; Motor Neurons; Oxaloacetic Acid; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Spinal Cord; Superoxide Dismutase; Tumor Necrosis Factor-alpha
PubMed: 34040085
DOI: 10.1038/s41598-021-90438-6 -
FEMS Microbiology Reviews Sep 2005In many organisms, metabolite interconversion at the phosphoenolpyruvate (PEP)-pyruvate-oxaloacetate node involves a structurally entangled set of reactions that... (Review)
Review
In many organisms, metabolite interconversion at the phosphoenolpyruvate (PEP)-pyruvate-oxaloacetate node involves a structurally entangled set of reactions that interconnects the major pathways of carbon metabolism and thus, is responsible for the distribution of the carbon flux among catabolism, anabolism and energy supply of the cell. While sugar catabolism proceeds mainly via oxidative or non-oxidative decarboxylation of pyruvate to acetyl-CoA, anaplerosis and the initial steps of gluconeogenesis are accomplished by C3- (PEP- and/or pyruvate-) carboxylation and C4- (oxaloacetate- and/or malate-) decarboxylation, respectively. In contrast to the relatively uniform central metabolic pathways in bacteria, the set of enzymes at the PEP-pyruvate-oxaloacetate node represents a surprising diversity of reactions. Variable combinations are used in different bacteria and the question of the significance of all these reactions for growth and for biotechnological fermentation processes arises. This review summarizes what is known about the enzymes and the metabolic fluxes at the PEP-pyruvate-oxaloacetate node in bacteria, with a particular focus on the C3-carboxylation and C4-decarboxylation reactions in Escherichia coli, Bacillus subtilis and Corynebacterium glutamicum. We discuss the activities of the enzymes, their regulation and their specific contribution to growth under a given condition or to biotechnological metabolite production. The present knowledge unequivocally reveals the PEP-pyruvate-oxaloacetate nodes of bacteria to be a fascinating target of metabolic engineering in order to achieve optimized metabolite production.
Topics: Bacteria; Gene Expression Regulation, Bacterial; Glucose; Oxaloacetates; Pentose Phosphate Pathway; Phosphoenolpyruvate; Pyruvic Acid
PubMed: 16102602
DOI: 10.1016/j.femsre.2004.11.002 -
IUBMB Life Jun 2017Iron-sulphur proteins are ancient and drive fundamental processes in cells, notably electron transfer and CO fixation. Iron-sulphur minerals with equivalent structures...
Iron-sulphur proteins are ancient and drive fundamental processes in cells, notably electron transfer and CO fixation. Iron-sulphur minerals with equivalent structures could have played a key role in the origin of life. However, the 'iron-sulphur world' hypothesis has had a mixed reception, with questions raised especially about the feasibility of a pyrites-pulled reverse Krebs cycle. Phylogenetics suggests that the earliest cells drove carbon and energy metabolism via the acetyl CoA pathway, which is also replete in Fe(Ni)S proteins. Deep differences between bacteria and archaea in this pathway obscure the ancestral state. These differences make sense if early cells depended on natural proton gradients in alkaline hydrothermal vents. If so, the acetyl CoA pathway diverged with the origins of active ion pumping, and ancestral CO fixation might have been equivalent to methanogens, which depend on a membrane-bound NiFe hydrogenase, energy converting hydrogenase. This uses the proton-motive force to reduce ferredoxin, thence CO . The mechanism suggests that pH could modulate reduction potential at the active site of the enzyme, facilitating the difficult reduction of CO by H . This mechanism could be generalised under abiotic conditions so that steep pH differences across semi-conducting Fe(Ni)S barriers drives not just the first steps of CO fixation to C1 and C2 organics such as CO, CH SH and CH COSH, but a series of similar carbonylation and hydrogenation reactions to form longer chain carboxylic acids such as pyruvate, oxaloacetate and α-ketoglutarate, as in the incomplete reverse Krebs cycle found in methanogens. We suggest that the closure of a complete reverse Krebs cycle, by regenerating acetyl CoA directly, displaced the acetyl CoA pathway from many modern groups. A later reliance on acetyl CoA and ATP eliminated the need for the proton-motive force to drive most steps of the reverse Krebs cycle. © 2017 IUBMB Life, 69(6):373-381, 2017.
Topics: Acetyl Coenzyme A; Archaea; Bacteria; Carbon Cycle; Carbon Dioxide; Catalysis; Citric Acid Cycle; Ferredoxins; Hydrogen-Ion Concentration; Hydrothermal Vents; Iron; Iron-Sulfur Proteins; Ketoglutaric Acids; Origin of Life; Oxaloacetic Acid; Protons; Pyruvic Acid
PubMed: 28470848
DOI: 10.1002/iub.1632 -
Journal of Bacteriology Dec 1964Benziman, Moshe (The Hebrew University of Jerusalem, Jerusalem, Israel), and N. Heller. Oxaloacetate decarboxylation and oxaloacetate-carbon dioxide exchange in...
Benziman, Moshe (The Hebrew University of Jerusalem, Jerusalem, Israel), and N. Heller. Oxaloacetate decarboxylation and oxaloacetate-carbon dioxide exchange in Acetobacter xylinum. J. Bacteriol. 88:1678-1687. 1964.-Extracts of Acetobacter xylinum, prepared by sonic treatment, were shown to catalyze the decarboxylation of oxaloacetate (OAA) to pyruvate and CO(2), and the exchange of C(14)-carbon dioxide into the beta-carboxyl of OAA. Fractionation of the extracts with ammonium sulfate resulted in a 10-fold increase of the specific activity of the enzyme system catalyzing the CO(2) exchange and OAA decarboxylation reactions. The purified preparation catalyzed the exchange of pyruvate-3-C(14) into OAA. Similar pH curves with a pH optimum of 5.6 were obtained for the CO(2) exchange and OAA decarboxylation reactions. Both reactions require the presence of Mn(2+) or Mg(2+) ions. OAA decarboxylation was more strongly inhibited than the exchange of CO(2) by dialysis or metal-chelating agents. Avidin did not inhibit either reaction. Adenosine triphosphate (ATP), adenosine diphosphate (ADP), guanosine triphosphate (GTP), guanosine diphosphate (GDP), pyrophosphate, or inorganic phosphate did not promote OAA decarboxylation and the CO(2)-exchange reaction catalyzed by the purified preparation. The purified preparation failed to catalyze the carboxylation of phosphoenolpyruvate in the presence of GDP, ADP, or inorganic phosphate, and that of pyruvate in the presence of ATP or GTP, even when supplemented with an OAA-trapping system. A scheme for OAA decarboxylation which could account for the observed exchange reactions and for the failure to obtain net fixation of CO(2) is proposed. The relation between the exchange reaction and the synthesis of cellulose from pyruvate by A. xylinum is discussed.
Topics: Acetates; Acetobacter; Adenosine Triphosphate; Carbon Dioxide; Carbon Isotopes; Cellulose; Chelating Agents; Decarboxylation; Diphosphates; Gluconacetobacter xylinus; Guanine Nucleotides; Hydrogen-Ion Concentration; Israel; Magnesium; Manganese; Metabolism; Oxaloacetates; Oxaloacetic Acid; Pharmacology; Pyruvates; Pyruvic Acid; Renal Dialysis; Research
PubMed: 14240957
DOI: 10.1128/jb.88.6.1678-1687.1964