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Ketolysis

Hyperketotic States Due To Inherited Defects Of Ketolysis.

Hyperketotic States Due To Inherited Defects Of Ketolysis.

Abstract From the description of 2 unrelated patients with succinyl-CoA transferase (3-OAT) deficiency and 1 patient with acetoacetyl-CoA thiolase (AAT) deficiency, we have attempted to draw the clinical and metabolic consequences of such defects. The association of recurrent attacks of severe ketoacidosis with blood glucose levels generally high or normal, low lactacidemia and low ammonemia is the most common presentation of these disorders. In 3-OAT deficiency, a potentially fatal disorder, there is a permanent ketosis with the only excretion of 3-hydroxybutyrate, acetoacetate and 3-hydroxyisovalerate. AAT patients usually excrete, in addition to the usual ketone bodies, 2-methyl-3-hydroxybutyrate and tiglylglycine; 2-methyl-acetoacetate may also be present. Both conditions can be identified by enzymatic analysis in cultured fibroblast. These disorders can mimic diabetic ketoacidosis or salicylism and can easily be missed. The knowledge of these ketolytic defects must severely question the complacent diagnosis of 'fasting ketoacidosis' or 'idiopathic ketotic hypoglycemia', mainly when severe metabolic acidosis is present. Continue reading >>

Disorders Of Ketogenesis And Ketolysis

Disorders Of Ketogenesis And Ketolysis

Published on behalf of Oxford University Press Published online September 2016 | e-ISBN: 9780190463083 | DOI: Continue reading >>

Ketolysis Defects

Ketolysis Defects

Summary The serum concentration of ketone bodies [acetoacetate (AA) + D 3-hydroxybutyrate (3OHB)] represents the balance between their production by the liver and their utilization by peripheral tissues. After a 24-h fast, in normal children aged between 1 and 7 years ketone body levels of 3–6 mmol/liter are reached [1–5]. By analogy to the definition of lactic acidosis, a ketoacidosis is considered to occur when concentrations of ketone bodies are greater than 7 mmol/liter [6]. Many metabolic disorders of childhood may lead to ketoacidosis including insulin-dependent diabetes, the inborn errors of branched-chain amino acid catabolism (MSUD, MMA, PA, IVA), the congenital lactic acidoses like multiple carboxylase and pyruvate carboxylase deficiencies, and inherited defects in enzymes of gluconeogenesis. In these four categories of disorder, hyperketosis is thought to be mainly related to an excess of ketone body production. As opposed to these disorders, hyperketotic states due to ketolytic defects are mainly associated with decreased peripheral ketone body utilization. 3-Oxoacid CoA transferase (3OAT) deficiency is a very rare autosomal recessive disorder characterized by recurrent attacks of severe ketoacidosis with or without hypoglycemia, low lactacidemia, and low ammonemia. Intravenous glucose infusion results in a rapid improvement. Investigation of urinary organic acids during attacks demonstrates the presence of high concentrations of 3OHB and AA only without any other specific organic acids. Clinical diagnosis depends on the evidence of a permanent ketosis both in urine (acetest+) and in plasma (3OHB+AA more than 0.2 mmol/l even in the postprandial period) with a tendency to increase from morning through the day. A fasting test results in a highly abnormal i Continue reading >>

Disorders Of Ketogenesis And Ketolysis

Disorders Of Ketogenesis And Ketolysis

Disorders of ketone body metabolism are characterized by episodes of metabolic decompensation. The initial episode usually occurs in the newborn period or early childhood during an infection with vomiting. The disorders of ketogenesis cause hypoglycemia and encephalopathy. Decompensation leads to severe ketoacidosis in defects of ketone body utilization (including MCT1 transporter deficiency). Treatment aims to prevent the catabolism that leads to decompensation. Prolonged fasting is avoided and glucose is provided, orally or intravenously, during illnesses. The risk of decompensation falls with age, particularly for disorders of ketolysis. There have, however, been some fatal episodes in adults with HMG-CoA lyase deficiency, including during pregnancy. Access to the complete content on Oxford Medicine Online requires a subscription or purchase. Public users are able to search the site and view the abstracts for each book and chapter without a subscription. Please subscribe or login to access full text content. If you have purchased a print title that contains an access token, please see the token for information about how to register your code. For questions on access or troubleshooting, please check our FAQs, and if you can't find the answer there, please contact us. Glut1 Deficiency (Glut1D, OMIM #606777) is caused by impaired glucose transport into the brain. The resulting cerebral “energy crisis” causes intractable seizures, developmental delay, and a complex movement disorder. The diagnosis is based on clinical features, low CSF glucose and/or mutations in the SLC2A1 gene. Paroxysmal exertion-induced dystonia (PED) and hereditary cryohydrocytosis have been described as allelic variants. Adults are increasingly being recognized through family pedigrees. The con Continue reading >>

Fig. 6. Ketolysis Pathway. Β -ohb: Β -hydroxybutyrate

Fig. 6. Ketolysis Pathway. Β -ohb: Β -hydroxybutyrate

Cognitive decline related to advancing age includes many sub-categories of diseases, some more or less well defined and understood. First, there is “normal” cognitive decline, which is gradual and progressive during aging and seems inevitable. When cognitive decline is large enough to disrupt the activities of daily life, a state of dementia is diagnosed. There are several types of dementia according to the etiology of cognitive decline: vascular dementia, which results from a circulatory disorder causing an obstruction of cerebral blood vessels which leads to the progressive degeneration of brain cells due to a lack of oxygen. Vascular dementia represents 20% of all cases of dementia. Lewis body dementia is an accumulation of α -synuclein protein within the cell and it represents 5 to 15% of neurodegenerative diseases. Frontotemporal dementia as the name suggests, is a degeneration of the region of the frontal and temporal anterior cortex. The reasons for this degeneration are not fully understood. Alzheimer's disease (AD) represents the majority of cases of dementia (65%) although its etiology is not known exactly, or rather multi-factorial. The most accepted theory in the medical community to explain the origin of AD is currently the accumulation of β -amyloid protein in the form of plaques accompanied by neurofibrillary tangles of tau protein that cause neuronal death and loss of brain matter. However, this theory is challenged for many reasons. The high profile failures of anti- amyloid interventions and lack of agreement on which form the β -amyloid is toxic and the mechanism by which this occurs force the scientific community to consider amyloid only as one part of a multi-factorial disease process including a variety of aggravating factors. A recent paper Continue reading >>

Ketogenesis

Ketogenesis

Ketogenesis pathway. The three ketone bodies (acetoacetate, acetone, and beta-hydroxy-butyrate) are marked within an orange box Ketogenesis is the biochemical process by which organisms produce a group of substances collectively known as ketone bodies by the breakdown of fatty acids and ketogenic amino acids.[1][2] This process supplies energy to certain organs (particularly the brain) under circumstances such as fasting, but insufficient ketogenesis can cause hypoglycemia and excessive production of ketone bodies leads to a dangerous state known as ketoacidosis.[3] Production[edit] Ketone bodies are produced mainly in the mitochondria of liver cells, and synthesis can occur in response to an unavailability of blood glucose, such as during fasting.[3] Other cells are capable of carrying out ketogenesis, but they are not as effective at doing so.[4] Ketogenesis occurs constantly in a healthy individual.[5] Ketogenesis takes place in the setting of low glucose levels in the blood, after exhaustion of other cellular carbohydrate stores, such as glycogen.[citation needed] It can also take place when there is insufficient insulin (e.g. in type 1 (but not 2) diabetes), particularly during periods of "ketogenic stress" such as intercurrent illness.[3] The production of ketone bodies is then initiated to make available energy that is stored as fatty acids. Fatty acids are enzymatically broken down in β-oxidation to form acetyl-CoA. Under normal conditions, acetyl-CoA is further oxidized by the citric acid cycle (TCA/Krebs cycle) and then by the mitochondrial electron transport chain to release energy. However, if the amounts of acetyl-CoA generated in fatty-acid β-oxidation challenge the processing capacity of the TCA cycle; i.e. if activity in TCA cycle is low due to low amo Continue reading >>

During This Time, The Biocyc Websites

During This Time, The Biocyc Websites

SRI International will be closed from close of business 22 Dec 2017 until opening of business 2 Jan 2018. Support issues logged while SRI is closed will be addressed when we re-open. (EcoCyc, HumanCyc, MetaCyc, BsubCyc) will be down for maintenance until noon Sunday, 31 Dec 2017 All times Pacific Standard Time Continue reading >>

Hyperketotic States Due To Inherited Defects Of Ketolysis

Hyperketotic States Due To Inherited Defects Of Ketolysis

Abstract From the description of 2 unrelated patients with succinyl-CoA transferase (3- OAT) deficiency and 1 patient with acetoacetyl-CoA thiolase (AAT) deficiency, we have attempted to draw the clinical and metabolic consequences of such defects. The association of recurrent attacks of severe ketoacidosis with blood glucose levels generally high or normal, low lactacidemia and low ammonemia is the most common presentation of these disorders. In 3-OAT deficiency, a potentially fatal disorder, there is a permanent ketosis with the only excretion of 3-hydroxybutyrate, acetoacetate and 3-hydroxyisovalerate. AAT patients usually excrete, in addition to the usual ketone bodies, 2-methyl-3-hydroxybutyrate and tiglylglycine; 2-methyl-acetoacetate may also be present. Both conditions can be identified by enzymatic analysis in cultured fibroblast. These disorders can mimic diabetic ketoacidosis or salicylism and can easily be missed. The knowledge of these ketolytic defects must severely question the complacent diagnosis of ‘fasting ketoacidosis’ or ‘idiopathic ketotic hypoglycemia’, mainly when severe metabolic acidosis is present. Article / Publication Details Continue reading >>

Hepatocellular Carcinoma Redirects To Ketolysis For Progression Under Nutrition Deprivation Stress

Hepatocellular Carcinoma Redirects To Ketolysis For Progression Under Nutrition Deprivation Stress

Cancer cells are known for their capacity to rewire metabolic pathways to support survival and proliferation under various stress conditions. Ketone bodies, though produced in the liver, are not consumed in normal adult liver cells. We find here that ketone catabolism or ketolysis is re-activated in hepatocellular carcinoma (HCC) cells under nutrition deprivation conditions. Mechanistically, 3-oxoacid CoA-transferase 1 (OXCT1), a rate-limiting ketolytic enzyme whose expression is suppressed in normal adult liver tissues, is re-induced by serum starvation-triggered mTORC2-AKT-SP1 signaling in HCC cells. Moreover, we observe that enhanced ketolysis in HCC is critical for repression of AMPK activation and protects HCC cells from excessive autophagy, thereby enhancing tumor growth. Importantly, analysis of clinical HCC samples reveals that increased OXCT1 expression predicts higher patient mortality. Taken together, we uncover here a novel metabolic adaptation by which nutrition-deprived HCC cells employ ketone bodies for energy supply and cancer progression. Compared with their normal counterparts, cancer cells are metabolically reprogrammed in order to obtain sufficient energy or additional stimuli to support rapid cell growth and proliferation1,2. While cancer cells are known to consume glucose, glutamine and fatty acids disproportionately for energy as well as carbon and nitrogen sources for anabolism, nutrient limitation often occurs during tumor development. Increasing evidence has demonstrated that cancer cells are widely open to additional nutrient sources under nutrition-limiting conditions3. Two groups reported recently that a variety of cancer types consume acetate avidly to fuel cancer growth4,5,6. More recently, Loo et al.7 documented that metastatic colorectal Continue reading >>

Aberrant Ketolysis Fuels Hepatocellular Cancer Progression

Aberrant Ketolysis Fuels Hepatocellular Cancer Progression

At odds with their normal counterparts, hepatocellular carcinoma cells efficiently utilize ketone bodies to proliferate despite serum deprivation. These findings, which have been recently published in Cell Research, identify a novel metabolic circuitry through which tumors successfully cope with adverse microenvironmental conditions. One of the most impressive features of malignant cells is their ability to adapt to prominent changes in the composition of the extracellular milieu1. At odds with their non-transformed counterparts, cancer cells are indeed able to proliferate in the absence of growth factors, under pronounced hypoxia, as well as when nutrients and amino acids are limited1. Throughout the past decade, work from several laboratories clarified that neoplastic cells facing adverse microenvironmental conditions can utilize a variety of metabolites to support catabolic and anabolic reactions, including (but presumably not limited to) glucose, acetate, lactate, creatine, glutamine, serine, glycine and fatty acids2. Thus, cancer cells generally rewire their metabolism, hence acquiring the capacity to utilize metabolites that are locally available to support tumor progression2. Although less universal and less specific than initially thought (meaning that different cancers can exhibit quite distinct metabolic shifts, and that at least some of the metabolic alterations that accompany malignancy are also found in highly proliferating non-transformed cells), such a rewiring process provides putative targets for the development of novel anticancer agents3. Recent work from Huafeng Zhang's group identifies a novel metabolic circuitry based on ketolysis through which hepatocellular carcinoma (HCC) cells proliferate in spite of adverse microenvironmental conditions4. Star Continue reading >>

Metabolic Profiles Of Ketolysis And Glycolysis In Malignant Gliomas: Possible Predictors Of Response To Ketogenic Diet Therapy.

Metabolic Profiles Of Ketolysis And Glycolysis In Malignant Gliomas: Possible Predictors Of Response To Ketogenic Diet Therapy.

e13048 Background: The enzymatic differences in energy metabolism between normal brain tissues and malignant gliomas formed the basis for animal model studies that showed increased survival in mice with orthotopically transplanted glioblastoma multiforme (GBM) treated with energy restricted ketogenic diet (ERKD). To test the hypothesis that human brain tumors may also be sensitive to ERKD, we used immunohistochemistry reactions on formalin fixed paraffin embedded tumor samples to evaluate for the presence of enzymes important for the metabolism of ketones and glucose. Methods: Immunoreactivities were graded using a semi-quantitative scale based on the percentage of positive cells: low positive<5% (LOW); intermediate (INT) 5-20%; and highly positive (HIGH) >20%. Focal non-neoplastic “normal” brain tissue present within the specimens served as positive internal controls. Results: Succinyl CoA: 3-oxoacid CoA transferase (OXCT1) and 3-hydroxybutyrate dehydrogenase 1 (BDH1) are mitochondrial enzymes important for metabolizing beta hydroxy butyrate, the main ketone in blood. Both of these enzymes were either decreased or absent (INT or LOW) concordantly in 14 of the 17 (82%) GBMs, and in 1 of 6 (17%) anaplastic astrocytomas (AA). Two of the enzymes in the glycolytic pathway hexokinase-2 and pyruvate kinase M2 were concordantly LOW or INT in only 3 of the 17 GBMs that also were LOW or INT for both OXCT1 and BDH1. The remaining brain tumors were positive for at least one of these glycolytic enzymes. Mitochondrial enzymes were not globally deficient. The mitochondrial enzyme acetyl CoA transferase (ACAT1) was present in 9 of the 14 GBM specimens that were LOW or INT for the mitochondrial enzymes OXCT1 and BDH1. Conclusions: Our data showing that many, but not all, malignant Continue reading >>

During This Time, The Biocyc Websites

During This Time, The Biocyc Websites

SRI International will be closed from close of business 22 Dec 2017 until opening of business 2 Jan 2018. Support issues logged while SRI is closed will be addressed when we re-open. (EcoCyc, HumanCyc, MetaCyc, BsubCyc) will be down for maintenance until noon Sunday, 31 Dec 2017 All times Pacific Standard Time Continue reading >>

Ketogenesis And Ketolysis Flashcards Preview

Ketogenesis And Ketolysis Flashcards Preview

During fasting, the glucagon/insulin ratio rises, causing cAMP levels to be elevated. Protein kinase A is activated and phosphorylates hormone-sensitive lipase (HSL), activating this enzyme. HSL-P initiates the mobilization of adipose triacylglycerol by removing a fatty acid. Other lipases then act, producing fatty acids and glycerol. Insulin stimulates the phosphatase that inactivates HSL in the fed state Continue reading >>

Ketone Body Metabolism

Ketone Body Metabolism

Ketone body metabolism includes ketone body synthesis (ketogenesis) and breakdown (ketolysis). When the body goes from the fed to the fasted state the liver switches from an organ of carbohydrate utilization and fatty acid synthesis to one of fatty acid oxidation and ketone body production. This metabolic switch is amplified in uncontrolled diabetes. In these states the fat-derived energy (ketone bodies) generated in the liver enter the blood stream and are used by other organs, such as the brain, heart, kidney cortex and skeletal muscle. Ketone bodies are particularly important for the brain which has no other substantial non-glucose-derived energy source. The two main ketone bodies are acetoacetate (AcAc) and 3-hydroxybutyrate (3HB) also referred to as β-hydroxybutyrate, with acetone the third, and least abundant. Ketone bodies are always present in the blood and their levels increase during fasting and prolonged exercise. After an over-night fast, ketone bodies supply 2–6% of the body's energy requirements, while they supply 30–40% of the energy needs after a 3-day fast. When they build up in the blood they spill over into the urine. The presence of elevated ketone bodies in the blood is termed ketosis and the presence of ketone bodies in the urine is called ketonuria. The body can also rid itself of acetone through the lungs which gives the breath a fruity odour. Diabetes is the most common pathological cause of elevated blood ketones. In diabetic ketoacidosis, high levels of ketone bodies are produced in response to low insulin levels and high levels of counter-regulatory hormones. Ketone bodies The term ‘ketone bodies’ refers to three molecules, acetoacetate (AcAc), 3-hydroxybutyrate (3HB) and acetone (Figure 1). 3HB is formed from the reduction of AcAc i Continue reading >>

Ketolysis

Ketolysis

Also found in: Encyclopedia. ketolysis [ke-tol´ĭ-sis] the splitting up of ketone bodies. adj., adj ketolyt´ic. Miller-Keane Encyclopedia and Dictionary of Medicine, Nursing, and Allied Health, Seventh Edition. © 2003 by Saunders, an imprint of Elsevier, Inc. All rights reserved. ketolysis /ke·tol·y·sis/ (ke-tol´ĭ-sis) the splitting up of ketone bodies.ketolyt´ic ketolysis (kē-tŏl′ĭ-sĭs) [″ + Gr. lysis, dissolution] The dissolution of acetone or ketone bodies. ketolytic, adjective ketolysis the splitting up of ketone bodies. Want to thank TFD for its existence? Tell a friend about us, add a link to this page, or visit the webmaster's page for free fun content. Link to this page: ketolysis Continue reading >>

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