scholarly journals Ketone body metabolism and cardiovascular disease

2013 ◽  
Vol 304 (8) ◽  
pp. H1060-H1076 ◽  
Author(s):  
David G. Cotter ◽  
Rebecca C. Schugar ◽  
Peter A. Crawford
Keyword(s):  
Cardiovascular Disease ◽  
Ketone Body ◽  
De Novo ◽  
Ketone Bodies ◽  
Tricarboxylic Acid Cycle ◽  
De Novo Lipogenesis ◽  
Short Supply ◽  
Nutritional Interventions ◽  
Diagnostic Strategies ◽  
Ketone Body Metabolism

Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short supply. The metabolism of ketone bodies interfaces with the tricarboxylic acid cycle, β-oxidation of fatty acids, de novo lipogenesis, sterol biosynthesis, glucose metabolism, the mitochondrial electron transport chain, hormonal signaling, intracellular signal transduction pathways, and the microbiome. Here we review the mechanisms through which ketone bodies are metabolized and how their signals are transmitted. We focus on the roles this metabolic pathway may play in cardiovascular disease states, the bioenergetic benefits of myocardial ketone body oxidation, and prospective interactions among ketone body metabolism, obesity, metabolic syndrome, and atherosclerosis. Ketone body metabolism is noninvasively quantifiable in humans and is responsive to nutritional interventions. Therefore, further investigation of this pathway in disease models and in humans may ultimately yield tailored diagnostic strategies and therapies for specific pathological states.

scholarly journals Regulation of glucose and ketone-body metabolism in brain of anaesthetized rats

1974 ◽  
Vol 138 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Neil B. Ruderman ◽  
Peter S. Ross ◽  
Michael Berger ◽  
Michael N. Goodman
Keyword(s):  
Glucose Uptake ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Acetyl Coa ◽  
Total Blood ◽  
Diabetic Ketosis ◽  
Pyruvate Oxidation ◽  
Ketone Body Metabolism ◽  
Arteriovenous Difference ◽  
The Brain

1. The effects of starvation and diabetes on brain fuel metabolism were examined by measuring arteriovenous differences for glucose, lactate, acetoacetate and 3-hydroxybutyrate across the brains of anaesthetized fed, starved and diabetic rats. 2. In fed animals glucose represented the sole oxidative fuel of the brain. 3. After 48h of starvation, ketone-body concentrations were about 2mm and ketone-body uptake accounted for 25% of the calculated O2 consumption: the arteriovenous difference for glucose was not diminished, but lactate release was increased, suggesting inhibition of pyruvate oxidation. 4. In severe diabetic ketosis, induced by either streptozotocin or phlorrhizin (total blood ketone bodies >7mm), the uptake of ketone bodies was further increased and accounted for 45% of the brain 's oxidative metabolism, and the arteriovenous difference for glucose was decreased by one-third. The arteriovenous difference for lactate was increased significantly in the phlorrhizin-treated rats. 5. Infusion of 3-hydroxybutyrate into starved rats caused marked increases in the arteriovenous differences for lactate and both ketone bodies. 6. To study the mechanisms of these changes, steady-state concentrations of intermediates and co-factors of the glycolytic pathway were determined in freeze-blown brain. 7. Starved rats had increased concentrations of acetyl-CoA. 8. Rats with diabetic ketosis had increased concentrations of fructose 6-phosphate and decreased concentrations of fructose 1,6-diphosphate, indicating an inhibition of phosphofructokinase. 9. The concentrations of acetyl-CoA, glycogen and citrate, a potent inhibitor of phosphofructokinase, were increased in the streptozotocin-treated rats. 10. The data suggest that cerebral glucose uptake is decreased in diabetic ketoacidosis owing to inhibition of phosphofructokinase as a result of the increase in brain citrate. 11. The inhibition of brain pyruvate oxidation in starvation and diabetes can be related to the accelerated rate of ketone-body metabolism; however, we found no correlation between the decrease in glucose uptake in the diabetic state and the arteriovenous difference for ketone bodies. 12. The data also suggest that the rates of acetoacetate and 3-hydroxybutyrate utilization by brain are governed by their concentrations in plasma. 13. The finding of very low concentrations of acetoacetate and 3-hydroxybutyrate in brain compared with plasma suggests that diffusion across the blood –brain barrier may be the rate-limiting step in their metabolism.

scholarly journals Ketone Body Metabolism in the Ischemic Heart

2021 ◽  
Vol 8 ◽  
Author(s):  
Stephen C. Kolwicz
Keyword(s):  
Ketone Body ◽  
Ketone Bodies ◽  
Ischemia Reperfusion ◽  
Ischemic Heart ◽  
Myocardial Infarctions ◽  
Ketogenic Diets ◽  
Health And Disease ◽  
Ketone Body Metabolism ◽  
Artery Disease ◽  
Fuel Source

Ketone bodies have been identified as an important, alternative fuel source in heart failure. In addition, the use of ketone bodies as a fuel source has been suggested to be a potential ergogenic aid for endurance exercise performance. These findings have certainly renewed interest in the use of ketogenic diets and exogenous supplementation in an effort to improve overall health and disease. However, given the prevalence of ischemic heart disease and myocardial infarctions, these strategies may not be ideal for individuals with coronary artery disease. Although research studies have clearly defined changes in fatty acid and glucose metabolism during ischemia and reperfusion, the role of ketone body metabolism in the ischemic and reperfused myocardium is less clear. This review will provide an overview of ketone body metabolism, including the induction of ketosis via physiological or nutritional strategies. In addition, the contribution of ketone body metabolism in healthy and diseased states, with a particular emphasis on ischemia-reperfusion (I-R) injury will be discussed.

scholarly journals Maximum activities of some enzymes of glycolysis, the tricarboxylic acid cycle and ketone-body and glutamine utilization pathways in lymphocytes of the rat

1982 ◽  
Vol 208 (3) ◽  
pp. 743-748 ◽  
Author(s):  
M. Salleh M. Ardawi ◽  
Eric A. Newsholme
Keyword(s):  
Ketone Body ◽  
Citrate Synthase ◽  
Ketone Bodies ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Maximum Activity ◽  
Graft Versus Host Reaction ◽  
Acid Cycle ◽  
Oxoglutarate Dehydrogenase

1. The maximum activity of hexokinase in lymphocytes is similar to that of 6-phosphofructokinase, but considerably greater than that of phosphorylase, suggesting that glucose rather than glycogen is the major carbohydrate fuel for these cells. Starvation increased slightly the activities of some of the glycolytic enzymes. A local immunological challenge in vivo (a graft-versus-host reaction) increased the activities of hexokinase, 6-phosphofructokinase, pyruvate kinase and lactate dehydrogenase, confirming the importance of the glycolytic pathway in cell division. 2. The activities of the ketone-body-utilizing enzymes were lower than those of hexokinase or 6-phosphofructokinase, unlike in muscle and brain, and were not affected by starvation. It is suggested that the ketone bodies will not provide a quantitatively important alternative fuel to glucose in lymphocytes. 3. Of the enzymes of the tricarboxylic acid cycle whose activities were measured, that of oxoglutarate dehydrogenase was the lowest, yet its activity (about 4.0μmol/min per g dry wt. at 37°C) was considerably greater than the flux through the cycle (0.5μmol/min per g calculated from oxygen consumption by incubated lymphocytes). The activity was decreased by starvation, but that of citrate synthase was increased by the local immunological challenge in vivo. It is suggested that the rate of the cycle would increase towards the capacity indicated by oxoglutarate dehydrogenase in proliferating lymphocytes. 4. Enzymes possibly involved in the pathway of glutamine oxidation were measured in lymphocytes, which suggests that an aminotransferase reaction(s) (probably aspartate aminotransferase) is important in the conversion of glutamate into oxoglutarate rather than glutamate dehydrogenase, and that the maximum activity of glutaminase is markedly in excess of the rate of glutamine utilization by incubated lymphocytes. The activity of glutaminase is increased by both starvation and the local immunological challenge in vivo. This last finding suggests that metabolism of glutamine via glutaminase is important in proliferating lymphocytes.

scholarly journals The Impact of Dietary Glycemic Index and Glycemic Load on Postprandial Lipid Kinetics, Dyslipidemia and Cardiovascular Risk

Nutrients ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2204 ◽  
Author(s):  
Vaia Lambadiari ◽  
Emmanouil Korakas ◽  
Vasilios Tsimihodimos
Keyword(s):  
Cardiovascular Disease ◽  
Glycemic Index ◽  
De Novo ◽  
Glycemic Load ◽  
Insulin Response ◽  
De Novo Lipogenesis ◽  
Atherogenic Dyslipidemia ◽  
Postprandial Lipid Metabolism ◽  
Postprandial Lipid ◽  
The Impact

Many recent studies have acknowledged postprandial hypetriglyceridemia as a distinct risk factor for cardiovascular disease. This dysmetabolic state is the result of the hepatic overproduction of very low-density lipoproteins (VLDLs) and intestinal secretion of chylomicrons (CMs), which leads to highly atherogenic particles and endothelial inflammation. Postprandial lipid metabolism does not only depend on consumed fat but also on the other classes of nutrients that a meal contains. Various mechanisms through which carbohydrates exacerbate lipidemia have been identified, especially for fructose, which stimulates de novo lipogenesis. Glycemic index and glycemic load, despite their intrinsic limitations, have been used as markers of the postprandial glucose and insulin response, and their association with metabolic health and cardiovascular events has been extensively studied with contradictory results. This review aims to discuss the importance and pathogenesis of postprandial hypertriglyceridemia and its association with cardiovascular disease. Then, we describe the mechanisms through which carbohydrates influence lipidemia and, through a brief presentation of the available clinical studies on glycemic index/glycemic load, we discuss the association of these indices with atherogenic dyslipidemia and address possible concerns and implications for everyday practice.

scholarly journals Effects of food deprivation on ketonaemia, ketogenesis and hepatic intermediary metabolism in the non-lactating dairy cow

1979 ◽  
Vol 178 (1) ◽  
pp. 35-44 ◽  
Author(s):  
G D Baird ◽  
R J Heitzman ◽  
I M Reid ◽  
H W Symonds ◽  
M A Lomax
Keyword(s):  
Dairy Cows ◽  
Food Deprivation ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Tricarboxylic Acid Cycle ◽  
Energy Charge ◽  
Fold Increase ◽  
Lactating Cows ◽  
A Value ◽  
Lactating Dairy Cows

1. The aim of this work was to investigate why non-lactating dairy cows are less susceptible to the development of ketonaemia during food deprivation than are dairy cows in early lactation. 2. The first experiment (Expt. A) consisted of determining the effect of 6 days of food deprivation on the concentrations of ketone bodies, and of metabolites related to the regulation of ketogenesis, in jugular blood and liver of non-lactating cows. 3. During the food deprivation, blood ketone-body concentrations rose significantly, but to a value that was only 16% of that achieved in lactating cows deprived of food for 6 days [Baird, Heitzman & Hibbitt (1972) Biochem. J. 128, 1311–1318]. 4. In the liver, food deprivation caused: a rise in ketone-body concentrations; a fall in the concentration of glycogen and of various intermediates of the Embden-Meyerhof pathway and the tricarboxylic acid cycle; an increase in cytoplasmic reduction; a decrease in the [total NAD+]/[total NADH] ratio; a decrease in energy charge. These changes were all qualitatively similar to those previously observed in the livers of the food-deprived lactating cows. 5. There appeared therefore to be a discrepancy in the food-deprived non-lactating cows between the absence of marked ketonaemia and the occurrence of metabolic changes within the liver suggesting increased hepatic ketogenesis. This discrepancy was partially resolved in Expt. B by the observation in two catheterized non-lactating cows that, although there was a 2-fold increase in hepatic ketogenesis during 6 days of food deprivation, ketogenesis from the splanchnic bed as a whole (i.e. gut and liver combined) declined slightly owing to cessation of gut ketogenesis.

KETONE BODY METABOLISM IN NUTRITIONAL MYOPATHY

1964 ◽  
Vol 42 (8) ◽  
pp. 1153-1160 ◽  
Author(s):  
K. J. Jenkins
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Pectoral Muscle ◽  
Acid Oxidation ◽  
Dystrophic Muscle ◽  
Liver Homogenates ◽  
Ketone Body Metabolism

A study was conducted on the metabolism of ketone bodies in tissue preparations from normal and dystrophic chicks. The data indicated that the production of ketone bodies in liver homogenates, as a result of fatty acid oxidation, was not markedly altered by development of the dystrophic condition. Whereas acetoacetate was oxidized by normal and degenerative pectoral muscle to approximately the same extent, utilization of β-hydroxybutyrate in dystrophic muscle was markedly poorer. In view of present concepts of the reactions involved in the metabolism of ketone bodies the results suggest that in the chick myopathy the conversion of β-hydroxybutyrate to acetoacetate may be impaired.

scholarly journals A high-MUFA diet alone does not affect ketone body metabolism, but reduces glycated hemoglobin when combined with exercise training in diabetic rats

2017 ◽  
Vol 9 (1) ◽  
pp. 31-40
Author(s):  
Juraiporn Somboonwong ◽  
Khunkhong Huchaiyaphum ◽  
Onanong Kulaputana ◽  
Phisit Prapunwattana
Keyword(s):  
Exercise Training ◽  
Ketone Body ◽  
Glycated Hemoglobin ◽  
Ketone Bodies ◽  
Transferase Activity ◽  
Nonesterified Fatty Acids ◽  
Regular Diet ◽  
Coa Transferase ◽  
Ketone Body Metabolism ◽  
Mufa Diet

Abstract Background Monounsaturated fat (MUFA) also has glucose-lowering action, but its effect on ketone bodies is unknown. Objectives To examine the effects of high-MUFA diet alone or in combination with exercise training, which can improve glucose and ketone body metabolism, in a rat model of diabetes. Methods Wistar rats were administered streptozotocin to induce diabetes and then randomly divided into five groups: sedentary rats fed a regular diet (1), a high-saturated-fat diet (2), a high-MUFA diet (3); and exercisetrained rats fed a regular diet (4), and a high-MUFA diet (5). Training was by a treadmill twice daily, 5 days/week. At 12 weeks, glucose, glycated hemoglobin (HbA1c), insulin, nonesterified fatty acids (NEFA), and β-hydroxybutyrate levels were measured in cardiac blood. Activity of the overall ketone synthesis pathway was determined in liver and 3-ketoacyl-CoA transferase activity determined in gastrocnemius muscle. Results A high-MUFA diet tended to lower plasma glucose without affecting other biochemical variables. Training did not change glucose metabolism, but significantly reduced serum NEFA. Only the high-MUFA diet plus training significantly decreased HbA1c levels. Hepatic ketone synthesis was decreased and 3-ketoacyl-CoA transferase activity was increased by training alone or in combination with a high-MUFA diet. Changes in NEFA, β-hydroxybutyrate, and the enzymatic activities in response to training plus a high-MUFA diet were comparable to those caused by training alone. Conclusion A high-MUFA diet alone does not alter ketone body metabolism. Combination of a MUFA-rich diet and exercise training is more effective than either MUFA or exercise alone for lowering HbA1c.

scholarly journals The peroxisomal transporter ABCD3 plays a major role in dicarboxylic fatty acid metabolism

2021 ◽  
Author(s):  
Pablo Ranea-Robles ◽  
Hongjie Chen ◽  
Brandon Stauffer ◽  
Chunli Yu ◽  
Dipankar Bhattacharya ◽  
...  
Keyword(s):  
Fatty Acids ◽  
De Novo ◽  
Ketone Bodies ◽  
De Novo Lipogenesis ◽  
Lipid Homeostasis ◽  
Hepatic Cholesterol Synthesis ◽  
Specific Subset

Peroxisomes metabolize a specific subset of fatty acids, which include dicarboxylic fatty acids (DCAs) generated by ω-oxidation. Data obtained in vitro suggest that the peroxisomal transporter ABCD3 (also known as PMP70) mediates the transport of DCAs into the peroxisome, but in vivo evidence to support this role is lacking. In this study, we studied an Abcd3 KO mouse model generated by CRISPR-Cas9 technology using targeted and untargeted metabolomics, histology, immunoblotting, and stable isotope tracing technology. We show that ABCD3 functions in DCA metabolism and uncover a novel role for this peroxisomal transporter in lipid metabolic homeostasis. The Abcd3 KO mouse presents with lipodystrophy, increased circulating free fatty acids, decreased ketone bodies, enhanced hepatic cholesterol synthesis and decreased hepatic de novo lipogenesis. Moreover, our study suggests that DCAs are metabolized by mitochondrial β-oxidation when ABCD3 is not functional, reflecting the importance of the metabolic compartmentalization and communication between peroxisomes and mitochondria. In summary, this study provides data on the role of the peroxisomal transporter ABCD3 in hepatic lipid homeostasis and DCA metabolism, and the consequences of peroxisomal dysfunction for the liver.

scholarly journals Differential Response of Hippocampal and Cerebrocortical Autophagy and Ketone Body Metabolism to the Ketogenic Diet

2021 ◽  
Vol 15 ◽  
Author(s):  
Daniela Liśkiewicz ◽  
Arkadiusz Liśkiewicz ◽  
Marta M. Nowacka-Chmielewska ◽  
Mateusz Grabowski ◽  
Natalia Pondel ◽  
...  
Keyword(s):  
Frontal Cortex ◽  
Ketogenic Diet ◽  
Ketone Body ◽  
Brain Aging ◽  
Ketone Bodies ◽  
Monocarboxylate Transporter ◽  
Proper Function ◽  
Monocarboxylate Transporter 1 ◽  
Coa Transferase ◽  
Ketone Body Metabolism

Experimental and clinical data support the neuroprotective properties of the ketogenic diet and ketone bodies, but there is still a lot to discover to comprehensively understand the underlying mechanisms. Autophagy is a key mechanism for maintaining cell homeostasis, and therefore its proper function is necessary for preventing accelerated brain aging and neurodegeneration. Due to many potential interconnections, it is possible that the stimulation of autophagy may be one of the mediators of the neuroprotection afforded by the ketogenic diet. Recent studies point to possible interconnections between ketone body metabolism and autophagy. It has been shown that autophagy is essential for hepatic and renal ketogenesis in starvation. On the other hand, exogenous ketone bodies modulate autophagy both in vitro and in vivo. Many regional differences occur between brain structures which concern i.e., metabolic responses and autophagy dynamics. The aim of the present study was to evaluate the influence of the ketogenic diet on autophagic markers and the ketone body utilizing and transporting proteins in the hippocampus and frontal cortex. C57BL/6N male mice were fed with two ketogenic chows composed of fat of either animal or plant origins for 4 weeks. Markers of autophagosome formation as well as proteins associated with ketolysis (BDH1—3-hydroxybutyrate dehydrogenase 1, SCOT/OXCT1—succinyl CoA:3-oxoacid CoA transferase), ketone transport (MCT1—monocarboxylate transporter 1) and ketogenesis (HMGCL, HMGCS2) were measured. The hippocampus showed a robust response to nutritional ketosis in both changes in the markers of autophagy as well as the levels of ketone body utilizing and transporting proteins, which was also accompanied by increased concentrations of ketone bodies in this brain structure, while subtle changes were observed in the frontal cortex. The magnitude of the effects was dependent on the type of ketogenic diet used, suggesting that plant fats may exert a more profound effect on the orchestrated upregulation of autophagy and ketone body metabolism markers. The study provides a foundation for a deeper understanding of the possible interconnections between autophagy and the neuroprotective efficacy of nutritional ketosis.

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