The Experts below are selected from a list of 5481 Experts worldwide ranked by ideXlab platform
Tetsuya Fukui - One of the best experts on this subject based on the ideXlab platform.
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high fat diet induced obesity stimulates Ketone Body utilization in osteoclasts of the mouse bone
Biochemical and Biophysical Research Communications, 2016Co-Authors: Masahiro Yamasaki, Shinya Hasegawa, Masahiko Imai, Noriko Takahashi, Tetsuya FukuiAbstract:Previous studies have shown that high-fat diet (HFD)-induced obesity increases the acetoacetyl-CoA synthetase (AACS) gene expression in lipogenic tissue. To investigate the effect of obesity on the AACS gene in other tissues, we examined the alteration of AACS mRNA levels in HFD-fed mice. In situ hybridization revealed that AACS was observed in several regions of the embryo, including the backbone region (especially in the somite), and in the epiphysis of the adult femur. AACS mRNA expression in the adult femur was higher in HFD-fed mice than in normal-diet fed mice, but this increase was not observed in high sucrose diet (HSD)-induced obese mice. In addition, HFD-specific increases were observed in the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and interleukin (IL)-6 genes. Moreover, we detected higher AACS mRNA expression in the differentiated osteoclast cells (RAW 264), and found that AACS mRNA expression was significantly up-regulated by IL-6 treatment only in osteoclasts. These results indicate the novel function of the Ketone Body in bone metabolism. Because the abnormal activation of osteoclasts by IL-6 induces bone resorption, our data suggest that AACS and Ketone bodies are important factors in the relationship between obesity and osteoporosis.
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acetoacetyl coa synthetase a Ketone Body utilizing enzyme is controlled by srebp 2 and affects serum cholesterol levels
Molecular Genetics and Metabolism, 2012Co-Authors: Shinya Hasegawa, Kazuki Noda, Akina Maeda, Masaru Matsuoka, Masahiro Yamasaki, Tetsuya FukuiAbstract:Ketone bodies have been regarded as an energy source that is mainly produced in the liver, and exported to extrahepatic tissues. However, Ketone bodies have also been suggested to be used during the lipogenesis by the Ketone Body-utilizing enzyme, acetoacetyl-CoA synthetase (AACS). To elucidate the physiological role of AACS in the liver, we investigated the mechanism of transcription of the AACS gene and performed knockdown experiments. We showed that SREBP-2 regulates the expression of AACS and that knockdown of AACS in vivo, by the hydrodynamics method, resulted in the reduction of total blood cholesterol. These results suggest that Ketone Body metabolism via AACS activity plays an important role in cholesterol homeostasis.
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different localization in rat brain of the novel cytosolic Ketone Body utilizing enzyme acetoacetyl coa synthetase as compared to succinyl coa 3 oxoacid coa transferase
Biochimica et Biophysica Acta, 2005Co-Authors: Mizuomi Ohnuki, Masahiro Yamasaki, Noriko Takahashi, Tetsuya FukuiAbstract:In lipogenic tissue cytosol, Ketone bodies are known to be activated by acetoacetyl-CoA synthetase (AACS) and incorporated into cholesterol and fatty acids. In order to investigate the physiological role of AACS in the brain, we examined the localization of AACS mRNA in rat brain by in situ hybridization using a labeled probe. High labeling was observed in the midbrain, pons/medulla, cerebral cortex, hippocampus and cerebellum, and the localization profile of AACS mRNA was different from that of succinyl-CoA:3-oxoacid CoA-transferase (SCOT), a mitochondrial Ketone Body-activating enzyme. In addition, the expression of AACS mRNA in the cerebellum was restricted primarily to glial cells, while in the cerebral cortex, it was restricted to neuronal cells. Streptozotocin treatment caused remarkable decreases in AACS mRNA levels in all regions where expression was observed, but changes in SCOT mRNA levels were not observed. These results suggest that the physiological role of AACS is different from that of SCOT and varies depending upon its localization in the brain.
Yuka Aoyama - One of the best experts on this subject based on the ideXlab platform.
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deficiency of 3 hydroxybutyrate dehydrogenase bdh1 in mice causes low Ketone Body levels and fatty liver during fasting
Journal of Inherited Metabolic Disease, 2020Co-Authors: Hiroki Otsuka, Yuka Aoyama, Takeshi Kimura, Mina Nakama, Elsayed Abdelkreem, Hideki Matsumoto, Yasuhiko Ago, Hidenori OhnishiAbstract:d-3-Hydroxy-n-butyrate dehydrogenase (BDH1; EC 1.1.1.30), encoded by BDH1, catalyzes the reversible reduction of acetoacetate (AcAc) to 3-hydroxybutyrate (3HB). BDH1 is the last enzyme of hepatic ketogenesis and the first enzyme of ketolysis. The hereditary deficiency of BDH1 has not yet been described in humans. To define the features of BDH1 deficiency in a mammalian model, we generated Bdh1-deficient mice (Bdh1 KO mice). Under normal housing conditions, with unrestricted access to food, Bdh1 KO mice showed normal growth, appearance, behavior, and fertility. In contrast, fasting produced marked differences from controls. Although Bdh1 KO mice survive fasting for at least 48 hours, blood 3HB levels remained very low in Bdh1 KO mice, and despite AcAc levels moderately higher than in controls, total Ketone Body levels in Bdh1 KO mice were significantly lower than in wild-type (WT) mice after 16, 24, and 48 hours fasting. Hepatic fat content at 24 hours of fasting was greater in Bdh1 KO than in WT mice. Systemic BDH1 deficiency was well tolerated under normal fed conditions but manifested during fasting with a marked increase in AcAc/3HB ratio and hepatic steatosis, indicating the importance of ketogenesis for lipid energy balance in the liver.
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deficiency of 3 hydroxybutyrate dehydrogenase bdh1 in mice causes low Ketone Body levels and fatty liver during fasting
Journal of Inherited Metabolic Disease, 2020Co-Authors: Hiroki Otsuka, Yuka Aoyama, Takeshi Kimura, Mina Nakama, Elsayed Abdelkreem, Hideki Matsumoto, Hidenori Ohnishi, Hideo SasaiAbstract:: D-3-hydroxy-n-butyrate dehydrogenase (BDH1; EC 1.1.1.30), encoded by BDH1, catalyzes the reversible reduction of acetoacetate (AcAc) to 3-hydroxybutyrate (3HB). BDH1 is the last enzyme of hepatic ketogenesis and the first enzyme of ketolysis. The hereditary deficiency of BDH1 has not yet been described in humans. To define the features of BDH1 deficiency in a mammalian model, we generated Bdh1-deficient mice (Bdh1 KO mice). Under normal housing conditions, with unrestricted access to food, Bdh1 KO mice showed normal growth, appearance, behavior and fertility. In contrast, fasting produced marked differences from controls. Although Bdh1 KO survive fasting for at least 48 hours, blood 3HB levels remained very low in Bdh1 KO mice, and despite AcAc levels moderately higher than in controls, total Ketone Body (TKB) levels in Bdh1 KO mice were significantly lower than in wild-type (WT) mice after 16, 24 and 48 hours fasting. Hepatic fat content at 24 hours of fasting was greater in Bdh1 KO than in WT mice. Systemic BDH1 deficiency was well tolerated under normal fed conditions but manifested during fasting with a marked increase in AcAc/3HB ratio and hepatic steatosis, indicating the importance of ketogenesis for lipid energy balance in the liver. This article is protected by copyright. All rights reserved.
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Ketone Body metabolism and its defects
Journal of Inherited Metabolic Disease, 2014Co-Authors: Toshiyuki Fukao, Grant A. Mitchell, Tomohiro Hori, Jorn Olive Sass, Kenji E Orii, Yuka AoyamaAbstract:Acetoacetate (AcAc) and 3-hydroxybutyrate (3HB), the two main Ketone bodies of humans, are important vectors of energy transport from the liver to extrahepatic tissues, especially during fasting, when glucose supply is low. Blood total Ketone Body (TKB) levels should be evaluated in the context of clinical history, such as fasting time and ketogenic stresses. Blood TKB should also be evaluated in parallel with blood glucose and free fatty acids (FFA). The FFA/TKB ratio is especially useful for evaluation of Ketone Body metabolism. Defects in ketogenesis include mitochondrial HMG-CoA synthase (mHS) deficiency and HMG-CoA lyase (HL) deficiency. mHS deficiency should be considered in non-ketotic hypoglycemia if a fatty acid beta-oxidation defect is suspected, but cannot be confirmed. Patients with HL deficiency can develop hypoglycemic crises and neurological symptoms even in adolescents and adults. Succinyl-CoA-3-oxoacid CoA transferase (SCOT) deficiency and beta-ketothiolase (T2) deficiency are two defects in ketolysis. Permanent ketosis is pathognomonic for SCOT deficiency. However, patients with “mild” SCOT mutations may have nonketotic periods. T2-deficient patients with “mild” mutations may have normal blood acylcarnitine profiles even in ketoacidotic crises. T2 deficient patients cannot be detected in a reliable manner by newborn screening using acylcarnitines. We review recent data on clinical presentation, metabolite profiles and the course of these diseases in adults, including in pregnancy.
Bouchra Gharib - One of the best experts on this subject based on the ideXlab platform.
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enhancement of l 3 hydroxybutyryl coa dehydrogenase activity and circulating Ketone Body levels by pantethine relevance to dopaminergic injury
BMC Neuroscience, 2010Co-Authors: Emilie Cornille, Michel Khrestchatisky, André Nieoullon, Max L. De Reggi, Mhamad Abouhamdan, Bouchra GharibAbstract:The administration of the Ketone bodies hydroxybutyrate and acetoacetate is known to exert a protective effect against metabolic disorders associated with cerebral pathologies. This suggests that the enhancement of their endogenous production might be a rational therapeutic approach. Ketone bodies are generated by fatty acid beta-oxidation, a process involving a mitochondrial oxido-reductase superfamily, with fatty acid-CoA thioesters as substrates. In this report, emphasis is on the penultimate step of the process, i.e. L-3-hydroxybutyryl-CoA dehydrogenase activity. We determined changes in enzyme activity and in circulating Ketone Body levels in the MPTP mouse model of Parkinson's disease. Since the active moiety of CoA is pantetheine, mice were treated with pantethine, its naturally-occurring form. Pantethine has the advantage of being known as an anti-inflammatory and hypolipidemic agent with very few side effects. We found that dehydrogenase activity and circulating Ketone Body levels were drastically reduced by the neurotoxin MPTP, whereas treatment with pantethine overcame these adverse effects. Pantethine prevented dopaminergic neuron loss and motility disorders. In vivo and in vitro experiments showed that the protection was associated with enhancement of glutathione (GSH) production as well as restoration of respiratory chain complex I activity and mitochondrial ATP levels. Remarkably, pantethine treatment boosted the circulating Ketone Body levels in MPTP-intoxicated mice, but not in normal animals. These finding demonstrate the feasibility of the enhancement of endogenous Ketone Body production and provide a promising therapeutic approach to Parkinson's disease as well as, conceivably, to other neurodegenerative disorders.
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Enhancement of L-3-hydroxybutyryl-CoA dehydrogenase activity and circulating Ketone Body levels by pantethine. Relevance to dopaminergic injury.
BMC Neuroscience, 2010Co-Authors: Emilie Cornille, Mhamad Abou-hamdan, Michel Khrestchatisky, André Nieoullon, Max L. De Reggi, Bouchra GharibAbstract:BACKGROUND: The administration of the Ketone bodies hydroxybutyrate and acetoacetate is known to exert a protective effect against metabolic disorders associated with cerebral pathologies. This suggests that the enhancement of their endogenous production might be a rational therapeutic approach. Ketone bodies are generated by fatty acid beta-oxidation, a process involving a mitochondrial oxido-reductase superfamily, with fatty acid-CoA thioesters as substrates. In this report, emphasis is on the penultimate step of the process, i.e. L-3-hydroxybutyryl-CoA dehydrogenase activity. We determined changes in enzyme activity and in circulating Ketone Body levels in the MPTP mouse model of Parkinson's disease. Since the active moiety of CoA is pantetheine, mice were treated with pantethine, its naturally-occurring form. Pantethine has the advantage of being known as an anti-inflammatory and hypolipidemic agent with very few side effects. RESULTS: We found that dehydrogenase activity and circulating Ketone Body levels were drastically reduced by the neurotoxin MPTP, whereas treatment with pantethine overcame these adverse effects. Pantethine prevented dopaminergic neuron loss and motility disorders. In vivo and in vitro experiments showed that the protection was associated with enhancement of glutathione (GSH) production as well as restoration of respiratory chain complex I activity and mitochondrial ATP levels. Remarkably, pantethine treatment boosted the circulating Ketone Body levels in MPTP-intoxicated mice, but not in normal animals. CONCLUSIONS: These finding demonstrate the feasibility of the enhancement of endogenous Ketone Body production and provide a promising therapeutic approach to Parkinson's disease as well as, conceivably, to other neurodegenerative disorders.
Niels Møller - One of the best experts on this subject based on the ideXlab platform.
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Ketone Body 3 hydroxybutyrate minor metabolite major medical manifestations
The Journal of Clinical Endocrinology and Metabolism, 2020Co-Authors: Niels MøllerAbstract:Ketone bodies - 3-hydroxybutyrate (3-OHB), acetoacetate, and acetone - are ancient, evolutionarily preserved, small fuel substrates, which uniquely can substitute and alternate with glucose under conditions of fuel and food deficiency. Once canonized as a noxious, toxic pathogen leading to ketoacidosis in patients with diabetes, it is now becoming increasingly clear that 3-OHB possesses a large number of beneficial, life-preserving effects in the fields of clinical science and medicine. 3-OHB, the most prominent Ketone Body, binds to specific hydroxyl-carboxylic acid receptors and inhibits histone deacetylase enzymes, free fatty acid receptors, and the NOD-like receptor protein 3 inflammasome, tentatively inhibiting lipolysis, inflammation, oxidative stress, cancer growth, angiogenesis, and atherosclerosis, and perhaps contributing to the increased longevity associated with exercise and caloric restriction. Clinically Ketone bodies/ketogenic diets have for a long time been used to reduce the incidence of seizures in epilepsy and may have a role in the treatment of other neurological diseases such as dementia. 3-OHB also acts to preserve muscle protein during systemic inflammation and is an important component of the metabolic defense against insulin-induced hypoglycemia. Most recently, a number of studies have reported that 3-OHB dramatically increases myocardial blood flow and cardiac output in control subjects and patients with heart failure. At the moment, scientific interest in Ketone bodies, in particular 3-OHB, is in a hectic transit and, hopefully, future, much needed, controlled clinical studies will reveal and determine to which extent the diverse biological manifestations of 3-OHB should be introduced medically.
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Ketone Body acetoacetate buffers methylglyoxal via a non enzymatic conversion during diabetic and dietary ketosis
Chemistry & Biology, 2017Co-Authors: Trine Salomon, Niels Møller, Christian Sibbersen, Jakob Hansen, Dieter Britz, Mads Svart, Thomas Schmidt Voss, Niels Gregersen, Karl Anker Jorgensen, Johan PalmfeldtAbstract:The α-oxoaldehyde methylglyoxal is a ubiquitous and highly reactive metabolite known to be involved in aging- and diabetes-related diseases. If not detoxified by the endogenous glyoxalase system, it exerts its detrimental effects primarily by reacting with biopolymers such as DNA and proteins. We now demonstrate that during ketosis, another metabolic route is operative via direct non-enzymatic aldol reaction between methylglyoxal and the Ketone Body acetoacetate, leading to 3-hydroxyhexane-2,5-dione. This novel metabolite is present at a concentration of 10%-20% of the methylglyoxal level in the blood of insulin-starved patients. By employing a metabolite-alkyne-tagging strategy it is clarified that 3-hydroxyhexane-2,5-dione is further metabolized to non-glycating species in human blood. The discovery represents a new direction within non-enzymatic metabolism and within the use of alkyne-tagging for metabolism studies and it revitalizes acetoacetate as a competent endogenous carbon nucleophile.
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Using positron emission tomography to study human Ketone Body metabolism: a review.
Metabolism: clinical and experimental, 2014Co-Authors: Nadia Bouteldja, Lone Thing Andersen, Niels Møller, Lars C. GormsenAbstract:Abstract Ketone bodies – 3-hydroxybutyrate and acetoacetate – are important fuel substrates, which can be oxidized by most tissues in the Body. They are synthesized in the liver and are derived from fatty acids released from adipose tissue. Intriguingly, under conditions of stress such as fasting, arterio-venous catheterization studies have shown that the brain switches from the use of almost 100% glucose to the use of > 50–60% Ketone bodies. A similar adaptive mechanism is observed in the heart, where fasting induces a shift toward Ketone Body uptake that provides the myocardium with an alternate fuel source and also favorably affects myocardial contractility. Within the past years there has been a renewed interest in Ketone bodies and the possible beneficial effects of fasting/semi-fasting/exercising and other “ketogenic” regimens have received much attention. In this perspective, it is promising that positron emission tomography (PET) techniques with isotopically labeled Ketone bodies, fatty acids and glucose offer an opportunity to study interactions between Ketone Body, fatty acid and glucose metabolism in tissues such as the brain and heart. PET scans are non-invasive and thus eliminates the need to place catheters in vascular territories not easily accessible. The short half-life of e.g. 11C-labeled PET tracers even allows multiple scans on the same study day and reduces the total radiation burden associated with the procedure. This short review aims to give an overview of current knowledge on Ketone Body metabolism obtained by PET studies and discusses the methodological challenges and perspectives involved in PET Ketone Body research.
Elsayed Abdelkreem - One of the best experts on this subject based on the ideXlab platform.
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deficiency of 3 hydroxybutyrate dehydrogenase bdh1 in mice causes low Ketone Body levels and fatty liver during fasting
Journal of Inherited Metabolic Disease, 2020Co-Authors: Hiroki Otsuka, Yuka Aoyama, Takeshi Kimura, Mina Nakama, Elsayed Abdelkreem, Hideki Matsumoto, Hidenori Ohnishi, Hideo SasaiAbstract:: D-3-hydroxy-n-butyrate dehydrogenase (BDH1; EC 1.1.1.30), encoded by BDH1, catalyzes the reversible reduction of acetoacetate (AcAc) to 3-hydroxybutyrate (3HB). BDH1 is the last enzyme of hepatic ketogenesis and the first enzyme of ketolysis. The hereditary deficiency of BDH1 has not yet been described in humans. To define the features of BDH1 deficiency in a mammalian model, we generated Bdh1-deficient mice (Bdh1 KO mice). Under normal housing conditions, with unrestricted access to food, Bdh1 KO mice showed normal growth, appearance, behavior and fertility. In contrast, fasting produced marked differences from controls. Although Bdh1 KO survive fasting for at least 48 hours, blood 3HB levels remained very low in Bdh1 KO mice, and despite AcAc levels moderately higher than in controls, total Ketone Body (TKB) levels in Bdh1 KO mice were significantly lower than in wild-type (WT) mice after 16, 24 and 48 hours fasting. Hepatic fat content at 24 hours of fasting was greater in Bdh1 KO than in WT mice. Systemic BDH1 deficiency was well tolerated under normal fed conditions but manifested during fasting with a marked increase in AcAc/3HB ratio and hepatic steatosis, indicating the importance of ketogenesis for lipid energy balance in the liver. This article is protected by copyright. All rights reserved.
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deficiency of 3 hydroxybutyrate dehydrogenase bdh1 in mice causes low Ketone Body levels and fatty liver during fasting
Journal of Inherited Metabolic Disease, 2020Co-Authors: Hiroki Otsuka, Yuka Aoyama, Takeshi Kimura, Mina Nakama, Elsayed Abdelkreem, Hideki Matsumoto, Yasuhiko Ago, Hidenori OhnishiAbstract:d-3-Hydroxy-n-butyrate dehydrogenase (BDH1; EC 1.1.1.30), encoded by BDH1, catalyzes the reversible reduction of acetoacetate (AcAc) to 3-hydroxybutyrate (3HB). BDH1 is the last enzyme of hepatic ketogenesis and the first enzyme of ketolysis. The hereditary deficiency of BDH1 has not yet been described in humans. To define the features of BDH1 deficiency in a mammalian model, we generated Bdh1-deficient mice (Bdh1 KO mice). Under normal housing conditions, with unrestricted access to food, Bdh1 KO mice showed normal growth, appearance, behavior, and fertility. In contrast, fasting produced marked differences from controls. Although Bdh1 KO mice survive fasting for at least 48 hours, blood 3HB levels remained very low in Bdh1 KO mice, and despite AcAc levels moderately higher than in controls, total Ketone Body levels in Bdh1 KO mice were significantly lower than in wild-type (WT) mice after 16, 24, and 48 hours fasting. Hepatic fat content at 24 hours of fasting was greater in Bdh1 KO than in WT mice. Systemic BDH1 deficiency was well tolerated under normal fed conditions but manifested during fasting with a marked increase in AcAc/3HB ratio and hepatic steatosis, indicating the importance of ketogenesis for lipid energy balance in the liver.
