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International Journal of Molecular... Feb 2023The increased metabolic activity of the heart as a pump involves a high demand of mitochondrial adenosine triphosphate (ATP) production for its mechanical and electrical... (Review)
Review
The increased metabolic activity of the heart as a pump involves a high demand of mitochondrial adenosine triphosphate (ATP) production for its mechanical and electrical activities accomplished mainly via oxidative phosphorylation, supplying up to 95% of the necessary ATP production, with the rest attained by substrate-level phosphorylation in glycolysis. In the normal human heart, fatty acids provide the principal fuel (40-70%) for ATP generation, followed mainly by glucose (20-30%), and to a lesser degree (<5%) by other substrates (lactate, ketones, pyruvate and amino acids). Although ketones contribute 4-15% under normal situations, the rate of glucose use is drastically diminished in the hypertrophied and failing heart which switches to ketone bodies as an alternate fuel which are oxidized in lieu of glucose, and if adequately abundant, they reduce myocardial fat delivery and usage. Increasing cardiac ketone body oxidation appears beneficial in the context of heart failure (HF) and other pathological cardiovascular (CV) conditions. Also, an enhanced expression of genes crucial for ketone break down facilitates fat or ketone usage which averts or slows down HF, potentially by avoiding the use of glucose-derived carbon needed for anabolic processes. These issues of ketone body utilization in HF and other CV diseases are herein reviewed and pictorially illustrated.
Topics: Humans; Ketone Bodies; Cardiovascular Diseases; Ketones; Heart Failure; Glucose; Adenosine Triphosphate
PubMed: 36834946
DOI: 10.3390/ijms24043534 -
Brain : a Journal of Neurology Jan 2024Alterations in brain energy metabolism have long been proposed as one of several neurobiological processes contributing to delirium. This is supported by previous...
Alterations in brain energy metabolism have long been proposed as one of several neurobiological processes contributing to delirium. This is supported by previous findings of altered CSF lactate and neuron-specific enolase concentrations and decreased glucose uptake on brain-PET in patients with delirium. Despite this, there are limited data on metabolic alterations found in CSF samples, and targeted metabolic profiling of CSF metabolites involved in energy metabolism has not been performed. The aim of the study was to investigate whether metabolites related to energy metabolism in the serum and CSF of patients with hip fracture are associated with delirium. The study cohort included 406 patients with a mean age of 81 years (standard deviation 10 years), acutely admitted to hospital for surgical repair of a hip fracture. Delirium was assessed daily until the fifth postoperative day. CSF was collected from all 406 participants at the onset of spinal anaesthesia, and serum samples were drawn concurrently from 213 participants. Glucose and lactate in CSF were measured using amperometry, whereas plasma glucose was measured in the clinical laboratory using enzymatic photometry. Serum and CSF concentrations of the branched-chain amino acids, 3-hydroxyisobutyric acid, acetoacetate and β-hydroxybutyrate were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). In total, 224 (55%) patients developed delirium pre- or postoperatively. Ketone body concentrations (acetoacetate, β-hydroxybutyrate) and branched-chain amino acids were significantly elevated in the CSF but not in serum among patients with delirium, despite no group differences in glucose concentrations. The level of 3-hydroxyisobutyric acid was significantly elevated in both CSF and serum. An elevation of CSF lactate during delirium was explained by age and comorbidity. Our data suggest that altered glucose utilization and a shift to ketone body metabolism occurs in the brain during delirium.
Topics: Humans; Aged, 80 and over; Glucose; Acetoacetates; 3-Hydroxybutyric Acid; Delirium; Tandem Mass Spectrometry; Hip Fractures; Brain; Lactates; Amino Acids, Branched-Chain
PubMed: 37658825
DOI: 10.1093/brain/awad296 -
Pain Dec 2022Methylglyoxal (MGO) is a reactive dicarbonyl byproduct of glycolysis implicated in a growing number of neuropathic pain conditions, including chemotherapy-induced...
Methylglyoxal (MGO) is a reactive dicarbonyl byproduct of glycolysis implicated in a growing number of neuropathic pain conditions, including chemotherapy-induced peripheral neuropathy, diabetic peripheral neuropathy, and radiculopathy with lumbar disk herniation. Recent studies show success in preclinical models treating these disorders with an interventional ketogenic diet. Here, we tested the hypothesis that a ketogenic diet modifies pathological MGO signaling as a mechanism underlying neuropathy improvement. We found that mice injected with MGO displayed nocifensive behaviors, whereas mice prefed a ketogenic diet were resistant to mechanical allodynia elicited by MGO. In addition, levels of circulating MGO were reduced in ketogenic diet-fed mice and negatively correlated with levels of the ketone body β-hydroxybutyrate (β-HB). Methylglyoxal is normally scavenged by the glyoxalase system, and ketogenic diet-fed mice displayed increased glyoxalase 1 activity compared with chow-fed control mice. Recent studies also suggest that ketone bodies contribute to MGO detoxification, consistent with a negative correlation between β-HB and MGO. To assess whether ketone bodies modified MGO-evoked nociception through direct MGO detoxification, we coincubated either acetoacetate or β-HB with MGO before injection. Mice receiving intraplantar MGO injection exhibit increased nociceptive behavior (lifting, licking, biting, and scratching), which was significantly reduced by coincubation with either acetoacetate or β-HB. Methylglyoxal increased phospho-extracellular signal-regulated kinase-positive cells in the spinal dorsal horn, and this evoked spinal activation was ameliorated by preincubation with acetoacetate or β-HB. These results suggest that a ketogenic diet and ketone bodies ameliorate MGO-evoked nociception, partially through detoxification of MGO, and provide rationale for therapeutic intervention with a ketogenic diet in MGO-driven pathologies.
Topics: Mice; Animals; Pyruvaldehyde; Diet, Ketogenic; Acetoacetates; Nociception; Magnesium Oxide; Ketone Bodies; 3-Hydroxybutyric Acid
PubMed: 35500286
DOI: 10.1097/j.pain.0000000000002667 -
Extreme Physiology & Medicine 2014Ketone bodies acetoacetate (AcAc) and D-β-hydroxybutyrate (βHB) may provide an alternative carbon source to fuel exercise when delivered acutely in nutritional form.... (Review)
Review
Ketone bodies acetoacetate (AcAc) and D-β-hydroxybutyrate (βHB) may provide an alternative carbon source to fuel exercise when delivered acutely in nutritional form. The metabolic actions of ketone bodies are based on sound evolutionary principles to prolong survival during caloric deprivation. By harnessing the potential of these metabolic actions during exercise, athletic performance could be influenced, providing a useful model for the application of ketosis in therapeutic conditions. This article examines the energetic implications of ketone body utilisation with particular reference to exercise metabolism and substrate energetics.
PubMed: 25379174
DOI: 10.1186/2046-7648-3-17 -
The Journal of Nutrition, Health & Aging Jan 2015The brain is one of the most energy-demanding organs in the body. It has evolved intricate metabolic networks to fulfill this need and utilizes a variety of substrates... (Review)
Review
The brain is one of the most energy-demanding organs in the body. It has evolved intricate metabolic networks to fulfill this need and utilizes a variety of substrates to generate ATP, the universal energy currency. Any disruption in the supply of energy results in various abnormalities including Alzheimer's disease (AD), a condition with markedly diminished cognitive ability. Astrocytes are an important participant in maintaining the cerebral ATP budget. However, under oxidative stress induced by numerous factors including aluminum toxicity, the ability of astroctyes to generate ATP is impaired due to dysfunctional mitochondria. This leads to globular, glycolytic, lipogenic and ATP-deficient astrocytes, cerebral characteristics common in AD patients. The reversal of these perturbations by such natural metabolites as pyruvate, α-ketoglutarate, acetoacetate and L-carnitine provides valuable therapeutic cues against AD.
Topics: Acetoacetates; Adenosine Triphosphate; Aluminum; Alzheimer Disease; Astrocytes; Brain; Carnitine; Humans; Ketoglutaric Acids; Mitochondria; Oxidative Stress; Pyruvic Acid
PubMed: 25560817
DOI: 10.1007/s12603-014-0511-7 -
Biosensors Dec 2023Ketones are well-known biomarkers of fat oxidation produced in the liver as a result of lipolysis. These biomarkers include acetoacetic acid and β-hydroxybutyric acid...
Ketones are well-known biomarkers of fat oxidation produced in the liver as a result of lipolysis. These biomarkers include acetoacetic acid and β-hydroxybutyric acid in the blood/urine and acetone in our breath and skin. Monitoring ketone production in the body is essential for people who use caloric intake deficit to reduce body weight or use ketogenic diets for wellness or therapeutic treatments. Current methods to monitor ketones include urine dipsticks, capillary blood monitors, and breath analyzers. However, these existing methods have certain disadvantages that preclude them from being used more widely. In this work, we introduce a novel acetone sensor device that can detect acetone levels in breath and overcome the drawbacks of existing sensing approaches. The critical element of the device is a robust sensor with the capability to measure acetone using a complementary metal oxide semiconductor (CMOS) chip and convenient data analysis from a red, green, and blue deconvolution imaging approach. The acetone sensor device demonstrated sensitivity of detection in the micromolar-concentration range, selectivity for detection of acetone in breath, and a lifetime stability of at least one month. The sensor device utility was probed with real tests on breath samples using an established blood ketone reference method.
Topics: Humans; Acetone; Body Fluids; Ketones; 3-Hydroxybutyric Acid; Biomarkers
PubMed: 38248381
DOI: 10.3390/bios14010004 -
Frontiers in Physiology 2017Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved...
Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved by following a high-fat, low-carbohydrate "ketogenic" diet, but adherence to such diets can be difficult. An alternative way to increase blood D-β-hydroxybutyrate (D-βHB) concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown. Here, healthy human volunteers took part in three randomized metabolic studies of drinks containing a ketone ester (KE); (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, or ketone salts (KS); sodium plus potassium βHB. In the first study, 15 participants consumed KE or KS drinks that delivered ~12 or ~24 g of βHB. Both drinks elevated blood D-βHB concentrations (D-βHB C: KE 2.8 mM, KS 1.0 mM, < 0.001), which returned to baseline within 3-4 h. KS drinks were found to contain 50% of the L-βHB isoform, which remained elevated in blood for over 8 h, but was not detectable after 24 h. Urinary excretion of both D-βHB and L-βHB was <1.5% of the total βHB ingested and was in proportion to the blood AUC. D-βHB, but not L-βHB, was slowly converted to breath acetone. The KE drink decreased blood pH by 0.10 and the KS drink increased urinary pH from 5.7 to 8.5. In the second study, the effect of a meal before a KE drink on blood D-βHB concentrations was determined in 16 participants. Food lowered blood D-βHB C by 33% (Fed 2.2 mM, Fasted 3.3 mM, < 0.001), but did not alter acetoacetate or breath acetone concentrations. All ketone drinks lowered blood glucose, free fatty acid and triglyceride concentrations, and had similar effects on blood electrolytes, which remained normal. In the final study, participants were given KE over 9 h as three drinks ( = 12) or a continuous nasogastric infusion ( = 4) to maintain blood D-βHB concentrations greater than 1 mM. Both drinks and infusions gave identical D-βHB AUC of 1.3-1.4 moles.min. We conclude that exogenous ketone drinks are a practical, efficacious way to achieve ketosis.
PubMed: 29163194
DOI: 10.3389/fphys.2017.00848 -
International Journal of Cardiology.... Dec 2019Acetoacetate is used as an alternative energy source in the heart, and has the potential to improve cardiac function. However, the prognostic impact of acetoacetate has...
BACKGROUND
Acetoacetate is used as an alternative energy source in the heart, and has the potential to improve cardiac function. However, the prognostic impact of acetoacetate has not been investigated in heart failure.
METHODS
This study enrolled consecutive 615 hospitalized patients with heart failure. We investigated the associations between circulating acetoacetate and clinical characteristics or prognosis in HF patients.
RESULTS
We divided the patients into two groups based on circulating acetoacetate levels (high group: acetoacetate ≥35 µmoL/L, n = 313; and low group: acetoacetate <35 µmoL/L, n = 302). The high group had an older age (68 vs. 65 years, P = 0.003) and higher log brain natriuretic peptide levels (2.43 vs. 2.23, P < 0.001) compared with the low group. In contrast, there were no significant differences in the prevalence of co-morbidities, including diabetes mellitus, chronic kidney disease, and anemia, between the two groups. During the median follow-up period of 328 days, 66 all-cause deaths occurred. The high group had a worse prognosis compared with the low group (Log rank, P = 0.041). In the Cox proportional hazard analysis, circulating acetoacetate levels (per 10 µmoL/L increase) were associated with all-cause mortality (hazard ratio 1.020, 95% confidence interval 1.010-1.030, P < 0.001).
CONCLUSIONS
Circulating acetoacetate is associated with all-cause mortality in patients with heart failure. These results provide new insights into the role of alternative cardiac metabolism in heart failure patients, and raise the possibility of acetoacetate as a novel biomarker to predict the prognosis of heart failure patients.
PubMed: 31890860
DOI: 10.1016/j.ijcha.2019.100432 -
Proceedings of the National Academy of... Nov 2019Ketone bodies, including β-hydroxybutyrate and acetoacetate, are important alternative energy sources during energy shortage. β-Hydroxybutyrate also acts as a...
Ketone bodies, including β-hydroxybutyrate and acetoacetate, are important alternative energy sources during energy shortage. β-Hydroxybutyrate also acts as a signaling molecule via specific G protein-coupled receptors (GPCRs); however, the specific associated GPCRs and physiological functions of acetoacetate remain unknown. Here we identified acetoacetate as an endogenous agonist for short-chain fatty acid (SCFA) receptor GPR43 by ligand screening in a heterologous expression system. Under ketogenic conditions, such as starvation and low-carbohydrate diets, plasma acetoacetate levels increased markedly, whereas plasma and cecal SCFA levels decreased dramatically, along with an altered gut microbiota composition. In addition, -deficient mice showed reduced weight loss and suppressed plasma lipoprotein lipase activity during fasting and eucaloric ketogenic diet feeding. Moreover, -deficient mice exhibited minimal weight decrease after intermittent fasting. These observations provide insight into the role of ketone bodies in energy metabolism under shifts in nutrition and may contribute to the development of preventive medicine via diet and foods.
Topics: Animals; Diet, Ketogenic; Fasting; HEK293 Cells; Humans; Ketone Bodies; Ligands; Lipid Metabolism; Lipoprotein Lipase; Mice; Mice, Inbred C57BL; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 31685604
DOI: 10.1073/pnas.1912573116 -
Neural Regeneration Research Dec 2018Glucose is the main energy substrate for neurons, however, at certain conditions, e.g. in starvation, these cells could also use ketone bodies. This approach is used in... (Review)
Review
Glucose is the main energy substrate for neurons, however, at certain conditions, e.g. in starvation, these cells could also use ketone bodies. This approach is used in clinical conditions as the ketogenic diet. The ketogenic diet is actually a biochemical model of fasting. It includes replacing carbohydrates by fats in daily meal. Synthesis of ketone bodies β-hydroxubutirate, acetoacetate and acetone begins once glycogen stores have depleted in the liver. The ketogenic diet can be used to treat clinical conditions, primarily epilepsy. The mechanism of neuroprotective action of ketogenic diet is not very clear. It is shown that ketone bodies influence neurons at three different levels, namely, metabolic, signaling and epigenetic levels. Ketone bodies are not always neuroprotective. Sometimes they can be toxic for the brain. Ketoacidosis which is a very dangerous complication of diabetes mellitus or alcoholism can be taken as an example. The exact mechanism of how neuroprotective properties of ketone bodies reverse to neurotoxic is yet to be established.
PubMed: 30323121
DOI: 10.4103/1673-5374.241442