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 >>

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 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 >>

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 >>

Hepatocellular Carcinoma Redirects To Ketolysis For Progression Under Nutrition Deprivation Stress.

Abstract 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. Continue reading >>

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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 >>

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 >>

Chapter 152. Disorders Of Ketolysis

Ketolysis involves esterification of acetylacetonate (AcAc) to AcAcCoA by succinyl-CoA: 3-oxoacid transferase (SCOT) and involves hydrolysis of AcAcCoA by 3-ketothiolase to form acetyl-CoA.1 SCOT deficiency is characterized by episodic ketoacidosis, often beginning in infancy, with increased blood ketone bodies even in the fed state. Diagnosis can be established by enzyme assay in fibroblasts or by mutation analysis, and prenatal diagnosis can be accomplished in the same manner. Mitochondrial 3-ketothiolase releases acetyl-CoA from acetoacetyl-CoA and from 2-methylacetoacetyl-CoA, an intermediate in isoleucine oxidation (see Chapter 156). Enzyme deficiency can present in infancy with hyperammonemia, metabolic acidosis, and severe ketosis, or later with fasting- or protein-induced episodes of vomiting, hepatomegaly, ketoacidosis, and encephalopathy. Urine organic acid analysis shows increased 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, and tiglylglycine, but they may be obscured during acute illnesses by 3-hydroxybutyrate (3HB) and acetoacetate (AcAc) and may be detectable only between episodes or after an oral load of isoleucine. Glycine levels are often elevated in blood and urine. While usually not necessary to establish a diagnosis, the enzyme defect can be demonstrated in fibroblasts and leukocytes, and probably in amniocytes for prenatal diagnosis. The gene encoding the enzyme has been cloned and localized to chromosome 11 (11q22.3-23.1), and a few disease-causing mutations have been identified. Acute episodes should be treated with intravenous glucose and sodium bicarbonate. A low-protein diet, coupled with avoidance of fasting, decreases the frequency and severity of acute episodes and permits normal growth and development if irreversible neurologic Continue reading >>

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 >>

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 >>

Ketogenesis & Ketolysis

2 Ketogenesis 3 Ketone bodies are formed from acetyl CoA resulting from β oxidation of FA in excess of optimal function of Kreb's cycle. the hepatic production of acetoacetate and β hydroxybutyrate is minimal and the concentration of these compounds in the blood is very low (does not exceed 1 mg% or <0.2 mM). 4 Steps synthesis of Ketone bodies: 5 (3 or β hydroxyl- 3or β methyl glutaryl CoA) 7 Acetoacetate produces β-hydroxybutyrate in 8 Both acetoacetate and β-hydroxybutyrate can be transported across the mitochondrial membrane and the plasma membrane of the liver cells, 10 Acetone is volatile and can not be detected in the blood. 12 Regulation of Ketone body synthesis: 13 Importance of Ketogenesis The brain normally uses glucose as the only fuel. After the diet has been changed to lower blood glucose for 3 days, the brain gets 25% of its energy from ketone bodies. After about 40 days, this goes up to 70%, but can not utilize FA. 14 Ketolysis 15 During glucose is in short supply (starvation) or in insulin deficiency, the mitochondria of Cardiac (70% of its energy) ,skeletal muscles and kidney can use free fatty acids as a source of energy. 16 Mechanism: 17 Activation of acetoacetate to acetoacetyl CoA occurs by one of two pathways: 20 Importance of ketolysis: 21 Energetics production from degradation of ketone bodies in peripheral tissue 22 which is necessary to convert acetoacetate into 2 acety1 CoA. 23 Ketosis (ketoacidosis) 24 Mechanism: This condition associated with decreased insulin relative to the anti insulin hormones, leading to increased lipolysis and release of FFA from adipose tissue as well as decreased oxidation of glucose by the liver. 25 This increases the uptake and oxidation of FA by the liver forming excess acetyl COA. 27 Effects of ketosis: If Continue reading >>

Invitae Ketolysis Disorders Panel

Test description The Invitae Ketolysis Disorders Panel analyzes 2 genes, ACAT1 and OXCT1, which are associated with disorders of impaired ketone body metabolism. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Additionally, identification of disease-causing variants provides accurate genetic counseling, recognition of at-risk family members and assessment of carrier status. Continue reading >>

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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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 >>

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 >>