Disorders of Ketogenesis and Ketolysis | SpringerLink Ketolysis in the brain is able to sustain sufficient energy supply, because bHB is a very efficient source of energy in terms of ATP molecules produced per oxygen molecule, even compared to glucose [111]. Peroxisome proliferator-activated receptor- activation inhibits langerhans cell function. The full -oxidation spiral consists of four steps that result in the generation of acetyl-CoA, NADH, and FADH 2 for each cycle (figure 5.9). Some other studies, however, did not confirm this promising outcome [173], which could indicate that numerous factors control the ability of cells to utilize ketone bodies in vivo and that sensitivity to their actions could depend on a particular cancer type, genetic mutation, or microenvironment conditions. Guest J., Garg M., Bilgin A., Grant R. Relationship between central and peripheral fatty acids in humans. Essent. Pelerin H., Jouin M., Lallemand M.S., Alessandri J.M., Cunnane S.C., Langelier B., Guesnet P. Gene expression of fatty acid transport and binding proteins in the blood-brain barrier and the cerebral cortex of the rat: Differences across development and with different DHA brain status. 17.3: Ketone Bodies - Biology LibreTexts Thompson H.J., McGinley J.N., Spoelstra N.S., Jiang W., Zhu Z., Wolfe P. Effect of dietary energy restriction on vascular density during mammary carcinogenesis. Activated PPAR induces leukotriene degradation through - and -oxidation, as well as microsomal hydroxylation, which was proposed as a mechanism of inflammation resolution in experimental models and in patients with infectious diseases [158,159,160,161]. Peroxisome proliferator-activated receptors (PPARs) and peroxisomes in rat cortical and cerebellar astrocytes. CPT1 activity is regulated by the concentration of malonyl-CoA, an initial intermediate of fatty acid synthesis; therefore, CPT1 serves a regulatory node between fatty acid oxidation and biosynthesis [4]. mTORC1 is engaged in the activation of nutrient and growth factor-stimulated protein biosynthesis, mainly by phosphorylation of two proteins: p70S6K1 and 4EBP1. Inborn Errors of Ketone Body Metabolism and Transport: An Update for Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity. Ahmed K., Tunaru S., Offermanns S. Gpr109a, gpr109b and gpr81, a family of hydroxy-carboxylic acid receptors. PPAR is a nuclear receptor, whose endogenous ligands are fatty acids and their derivatives [16]. The complexes differ in their response to nutrient-induced signaling and rapamycin sensitivity. PPAR is the chief transcription factor responsible for the induction of the majority of the genes necessary for fatty acid transport, uptake and oxidation, as well as ketone body biosynthesis and import [10,11,12,13,14,15]. Providing exogenous energy sources alternative to glucose (such as ketone bodies) during this period may improve mitochondrial function and therefore protect neurons from apoptosis after ischemia and TBI episodes [139]. Fatty acid oxidation product, acetyl-CoA is the substrate for ketogenesis and the first step involves condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA in the reaction catalyzed by acetoacetyl-CoA thiolase (ACAT1, EC 2.3.1.9; Figure 1). Similarly, administration of AC-1202 compound, which consists of medium chain triglycerides used to induce a mild ketosis even in the presence of carbohydrates in diet, significantly improved the condition of AD patients with a higher risk of AD development (with the epsilon 4 variant of ApoE gene) compared to placebo [130]. The initial episode usually occurs in the newborn period or early childhood during an infection with vomiting. Whereas T2 promotes ketolysis in extrahepatic tissues, in liver it participates in ketogenesis by converting acetyl-CoA to acetoacetyl-CoA. Its unique property of increasing the redox potential between NADH/NAD (respiratory complex I) and ubiquinone/ubiquinon earned bHB a distinct name of superfuel [3,111,112]. Benign epithelial prostate cells are capable of fatty acid -oxidation and can be rescued by bHB addition during glucose starvation, whereas the more aggressive cells lose metabolic plasticity and cannot switch to bHB metabolism [179]. In addition, fenofibrate treatment demonstrated excellent neuroprotective effects against cerebral ischemia-reperfusion injury through its anti-oxidant and anti-inflammatory activities [164], and also reduced memory and learning deficits in rats subjected to global cerebral ischemia [165]. Alberti K.G., Johnston D.G., Gill A., Barnes A.J., Orskov H. Hormonal regulation of ketone-body metabolism in man. . Prins M.L., Fujima L.S., Hovda D.A. 1. Currently, the ketogenic diet is an adjunct therapy of choice, supporting the pharmacological treatment of epilepsy, or as a principal treatment method in drug-resistant cases, highlighting the efficacy in decreasing seizure frequency, especially in children [116,117]. Metabolic adaptation to prolonged fasting in humans is based both on coordinated responses of vital organs, mainly liver, kidneys and muscles, and on restoring nutritional preferences at the cellular level. Branched-chain amino acids: Enzyme and substrate regulation. In contrast to mice, in humans FGF21 does not regulate an immediate starvation response and its blood level does not rise until 710 days of fasting, when bHB plasma levels are already 70-fold higher than in fed state [53,54]. Since HCARs are also found on certain cells of the immune system such as macrophages and microglia, it is likely that ketone bodies modulate inflammatory responses. Kostiuk M.A., Keller B.O., Berthiaume L.G. Hydroxymethylglutaryl CoA (HMG CoA): A molecule created in the first step of the production of ketone bodies from acetyl-CoA. 1Department of Food Biotechnology, Faculty of Food Technology, University of Agriculture, ul. Vanitallie T.B., Nonas C., di Rocco A., Boyar K., Hyams K., Heymsfield S.B. Prins M.L., Hovda D.A. Brain metabolism during fasting. FGF21 and the late adaptive response to starvation in humans. Metabolic regulation in erythroid differentiation by systemic If pharmaceuticals, such as fenofibrate, are able to reprogram cancer metabolism towards ketogenesis while simultaneously blocking proliferation, this might be beneficial from a therapeutic point of view, especially in conditions where inflammation and associated edema are particularly dangerous, as seen in gliomas and other brain tumors. These intriguing new roles for ketone bodies may reveal how these molecules exert their effects on both cellular processes and metabolism. FormalPara Ketogenesis and Ketolysis During fasting, ketone bodies (KB) are an important fuel for many tissues, including cardiac and skeletal muscle. It instead burns fat, thus making ketones which can be used for fuel. This process begins with 2 acetyl-CoA in the mitochondria of hepatocytes. The studies by Lowe et al. Additionally, mTORC1 stimulates lipogenesis through the activation of sterol response element binding protein (SREBP) [59,60,61]. Clinical studies have revealed that medium chain triglycerides, an important component of the ketogenic diet, improve memory performance in patients with AD, which is exhibited in a positive correlation between blood bHB levels and improvement in Alzheimers Disease Assessment Scale-Cognitive Subscale (ADAS-cog) score [129]. In vitro treatment of cultured cells with bHB induces dose-dependent hyperacetylation of histones, which is similar to the in vivo hyperacetylation effects seen in the kidneys of mice following infusion of bHB via osmotic pump [67]. In the absence of sufficient carbohydrates for glycolysis, ample ATP can be produced from ketone bodies via ketogenesis. Xu K., Liu P., Wei W. Mtor signaling in tumorigenesis. Ketolysis is the process of catabolizing ketones, the opposite of ketogenesis which is the process of synthesizing ketones. Arachidonic acid derived inflammatory mediators, such as leukotrienes LTB4 and LTA4 are natural PPAR agonists [158]. Hildebrandt L.A., Spennetta T., Elson C., Shrago E. Utilization and preferred metabolic pathway of ketone bodies for lipid synthesis by isolated rat hepatoma cells. In more recent studies, bHB inhibited HDACs 1, 3 and 4 in vitro with an IC50 of 25 mM [67], which is both attainable through ketogenic diets, prolonged fasting or exhaustive exercise (0.53 mM) [2,70,71] and free from the harm associated with pathogenic ketoacidosis (1025 mM) [72]. Disorders of Ketogenesis and Ketolysis Andrew A. M. Morris Chapter 2979 Accesses 1 Citations Zusammenfassung Disorders of ketone body metabolism present either in the first few days of life or later in childhood, during an infection or some other metabolic stress. Cerebral metabolic response to traumatic brain injury sustained early in development: A 2-deoxy-. Chang Y.L., Gao H.W., Chiang C.P., Wang W.M., Huang S.M., Ku C.F., Liu G.Y., Hung H.C. Human mitochondrial NADP(+)-dependent malic enzyme participates in cutaneous melanoma progression and invasion. MTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Capacity for substrate utilization in oxidative metabolism by neurons, astrocytes, and oligodendrocytes from developing brain in primary culture. Negative and positive regulation of gene expression by mouse histone deacetylase 1. Epigenetic effects of both sodium butyrate and bHB exerted through the inhibition of HDAC3 are crucially important for regulation of FGF21 expression in newborn and adult mice [73,74]. The .gov means it's official. Nojima H., Tokunaga C., Eguchi S., Oshiro N., Hidayat S., Yoshino K., Hara K., Tanaka N., Avruch J., Yonezawa K. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mtor substrates p70 S6 kinase and 4E-BP1 through their tor signaling (TOS) motif. Dueregger A., Schopf B., Eder T., Hofer J., Gnaiger E., Aufinger A., Kenner L., Perktold B., Ramoner R., Klocker H., et al. Hirschey M.D., Shimazu T., Capra J.A., Pollard K.S., Verdin E. SIRT1 and SIRT3 deacetylate homologous substrates: ACECS1,2 and HMGCS1,2. The mode of action of hormones and growth factors involves transcriptional reprogramming to provide expression of the proper enzymatic machinery for ketogenesis and ketolysis. Elevation of glucagon levels, by hepatic perfusion or injections of rats with mannoheptulose, resulted in a significant increase in HMGCS2 activity and ketone body production. A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting. Ketogenesis is regulated in multiple stages, and a nuclear receptor peroxisome proliferator. Ketogenesis occurs primarily in the liver, whereas ketolysis occurs in non-liver cells, especially in the heart, brain, and skeletal muscle. The recent insights into the function of ACAT1: A possible - PubMed Recently, a hypothesis on the beneficial effects of the ketogenic diet in other neurological disorders, such as Alzheimers Disease (AD) or Parkinsons Disease (PD), has been widely discussed [127,128]. De Feyter H.M., Behar K.L., Rao J.U., Madden-Hennessey K., Ip K.L., Hyder F., Drewes L.R., Geschwind J.F., de Graaf R.A., Rothman D.L. The most important change in the systemic metabolism during fasting is triggered by glucagon and involves the mobilization of lipids stored in adipose tissue and break down of triglycerides to free fatty acids and glycerol [1,2]. White H., Venkatesh B. Ketone body supply and metabolism is particularly important in the brain. Hyperketonemia is a condition with elevated blood levels of acetoacetate (AA), 3--hydroxybutyrate (BHB), and acetone. Molecular Mechanisms for Ketone Body Metabolism, Signaling Functions Ketolytic and glycolytic enzymatic expression profiles in malignant gliomas: Implication for ketogenic diet therapy. De Virgilio A., Greco A., Fabbrini G., Inghilleri M., Rizzo M.I., Gallo A., Conte M., Rosato C., Ciniglio Appiani M., de Vincentiis M. Parkinsons disease: Autoimmunity and neuroinflammation. In hepatocytes in the liver, fatty acids (FAs) are normally transformed into acetyl-CoA, which can then enters the TCA (Krebs) cycle for energy production. Johnson C.A., Turner B.M. The high rate of TCA gradually reduces the pool of oxaloacetate, which limits transamination of glutamate to aspartate (by oxaloacetate/-ketoglutarate aminotransferases). Erickson A., Moreau R. The regulation of FGF21 gene expression by metabolic factors and nutrients. Hoffmann K., Czapp M., Loscher W. Increase in antiepileptic efficacy during prolonged treatment with valproic acid: Role of inhibition of histone deacetylases? The process most likely involves: (1) a passive diffusion and a flip-flop mechanism [92]; (2) protein-mediated transport through fatty acid transporters FATP 1-6, fatty acid translocase CD36 or caveolin-1 or Mfsd2a [91,93,94,95]; or transport as (3) a phospholipid constituent [96,97,98] or (4) in lipoproteins [99]. This approach turned out to be successful in treating malignant gliomas in experimental animals [194,195,196,197,198], and more importantly, for brain tumor patients [199,200,201]. Rhee J., Inoue Y., Yoon J.C., Puigserver P., Fan M., Gonzalez F.J., Spiegelman B.M. A ketogenic diet increases transport and oxidation of ketone bodies in RG2 and 9l gliomas without affecting tumor growth. Phoenix K.N., Vumbaca F., Fox M.M., Evans R., Claffey K.P. Zhou W., Mukherjee P., Kiebish M.A., Markis W.T., Mantis J.G., Seyfried T.N. Ketogenesis and Ketogenolysis. Insulin, which is the main anabolic hormone, is principally important: in the presence of insulin ketogenesis is strongly inhibited, even when catabolic hormones are also secreted. Examples of positive regulators include: CREB, SP1, COUP-TF and forkhead familyrelated transcription factors DKHRL1 and Foxa2 [21,25,26,27]. Glucose and lactate supply to the synapse. Barros L.F., Deitmer J.W. Glucagon, in addition to its positive effect on the delivery of free fatty acids to liver, also sharply decreased succinyl-CoA levels and HMGCS2 succinylation, which resulted in a strong activation of ketogenesis. Eyal S., Yagen B., Sobol E., Altschuler Y., Shmuel M., Bialer M. The activity of antiepileptic drugs as histone deacetylase inhibitors. Quant P.A., Tubbs P.K., Brand M.D. Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case report. Huth W., Jonas R., Wunderlich I., Seubert W. On the mechanism of ketogenesis and its control. Turko I.V., Marcondes S., Murad F. Diabetes-associated nitration of tyrosine and inactivation of succinyl-COA:3-oxoacid COA-transferase. This particular modification occurs spontaneously in a palmitoyl-CoA concentration dependent manner, and surprisingly, does not require transferase activity. Permeability changes in the blood-brain barrier: Causes and consequences. The ketogenic diet; fatty acids, fatty acid-activated receptors and neurological disorders. Mitchell R.W., Hatch G.M. . Effect of beta-hydroxybutyrate, a cerebral function improving agent, on cerebral hypoxia, anoxia and ischemia in mice and rats. Interestingly, the same substrates may also act as inhibitors when they are present within a certain range of concentrations [35]. Martinez-Outschoorn U.E., Lin Z., Whitaker-Menezes D., Howell A., Lisanti M.P., Sotgia F. Ketone bodies and two-compartment tumor metabolism: Stromal ketone production fuels mitochondrial biogenesis in epithelial cancer cells. Guzman M., Blazquez C. Ketone body synthesis in the brain: Possible neuroprotective effects. ); ude.cshusl@ssierk (K.R.). Motojima K. Differential effects of PPAR activators on induction of ectopic expression of tissue-specific fatty acid binding protein genes in the mouse liver. KBs participate in various cellular processes as signaling molecules. Figure 17.3. Mishra A., Chaudhary A., Sethi S. Oxidized -3 fatty acids inhibit NF-B activation via a PPAR-dependent pathway. The gradual accumulation of experimental data will allow us to gain a better understanding of the role of ketone bodies in both physiological and pathological circumstances, and may open up new opportunities for their therapeutic application against metabolic and inflammatory diseases, as well as cancer. Ketogenesis and ketolysis are regulated by the key rate-limiting enzymes, 3-hydroxy-3-methylglutaryl-CoA synthase 2 and succinyl-CoA:3-oxoacid-CoA transferase, respectively. Gottlicher M., Minucci S., Zhu P., Kramer O.H., Schimpf A., Giavara S., Sleeman J.P., Lo Coco F., Nervi C., Pelicci P.G., et al. These effects may be especially important since glucose infusion has been reported to increase oxidative stress and exert adverse effects [134]. A specific BCKD kinase phosphorylates E1 and inactivates the whole complex, which is also sensitive to allosteric inhibition by NADH and CoA esters (isobutyryl-CoA, methylbutyryl-CoA and isovaleryl-CoAall three being the intermediates of the BCAA degradation pathway). MCT1 is a ubiquitously expressed gene that contains PPRE in its promoter and is strongly transactivated by PPAR during fasting or in response to synthetic PPAR ligands [10]. official website and that any information you provide is encrypted Ketogenesis requires efficient mitochondrial -oxidation of fatty acids. Prins M.L., Matsumoto J.H. PPAR-RXR complex recruits variety of co-activator proteins with a histone acetyltransferase activity, that belong to the CBP/p300 or SRC/p160 families (reviewed in [17]). Energy substrates for brain during fasting. Both ketogenesis and ketolysis are regulated at the whole-body level by the endocrine system, with insulin and glucagon playing a central role in preventing and facilitating ketogenesis and ketolysis, respectively ( McGarry and Foster, 1977 ). PPAR is necessary for launching the ketogenic transcriptional program, but HMGCS2 is a nodal point in the ketogenic pathway and is strictly controlled by other transcription factors and various posttranslational mechanisms. Yudkoff M., Daikhin Y., Melo T.M., Nissim I., Sonnewald U., Nissim I. Patients with HL deficiency can develop hypoglycemic crises and neurological symptoms even . Although this receptor is expressed in the brain, the effects of bHB on its function in that tissue are not as well defined [78]. I. Nomenclature and rate equations. Ketogenesis is an important evolutionary achievement of mammals, especially primates. These intermediates are strong inhibitors of fatty acid oxidation and ketone body formation in liver and other ketogenic tissues. Zuccoli G., Marcello N., Pisanello A., Servadei F., Vaccaro S., Mukherjee P., Seyfried T.N. These exciting new data reveal that ketone bodies have intrinsic signaling capacities that in some cases may impact cellular or organismal metabolism, and in others, affect processes such as inflammation, which are known to be involved in certain neurological conditions such as Alzheimers, Parkinsons, and brain cancers [80,81,82]. Palmitoylation of HMGCS2 is a particularly interesting example of protein posttranslational modification that influences both the interaction with other proteins, such as PPAR, and the subsequent regulation of transcription. 3-Oxo acid coenzyme a transferase activity in brain and tumors of the nervous system. McGarry J.D., Mannaerts G.P., Foster D.W. A possible role for malonyl-COA in the regulation of hepatic fatty acid oxidation and ketogenesis. Lundasen T., Hunt M.C., Nilsson L.M., Sanyal S., Angelin B., Alexson S.E., Rudling M. PPAR is a key regulator of hepatic FGF21. than ketolysis; episodic ketoacidosis is, therefore, the only consistent biochemical abnormality in SCOT deficiency. FOIA The latter is accomplished by phosphorylation and inactivation of the two AMPK canonical target proteins: acetyl-CoA carboxylase (ACC) and HMG-CoA reductase (HMGCR), the rate limiting enzymes of fatty acid and steroid synthesis, respectively [56]. This hypothesis is further supported by experimental evidence that a short-chain, branched fatty acid valproate and its numerous analogues, which are widely used as anti-epileptic drugs, indeed do activate PPAR [118,119]. AMPK and mTOR complex 1 (mTORC1) respond to nutrient supply and cellular energy status. Transcription coactivators for peroxisome proliferator-activated receptors. Ketosis Definition Ketosis means a metabolic state in our body that is characterized by detectable ketone levels. KBs bind to G protein-coupled receptors. 5-Aminoimidazole-4-carboxamide ribonucleoside. Croset M., Brossard N., Polette A., Lagarde M. Characterization of plasma unsaturated lysophosphatidylcholines in human and rat. It remains to be elucidated how this competition affects overall HMGCS2 function. The site is secure. Purification and characterization of the AMP-activated protein kinase. Breast cancer cells retain the capacity to perform oxidative metabolism at a high rate and take advantage of ketolysis to support their growth and progression [184]. However, in animals with constitutively active hepatic mTORC1, ketogenesis does not occur due to the block of the PPAR-mediated expression of ketogenic genes. The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Rodriguez J.C., Gil-Gomez G., Hegardt F.G., Haro D. Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase gene by fatty acids. However, some studies indicate that despite the presence of ketolytic enzymes, the ability of ketone body utilization is lost during progression of malignant transformation [179]. After entering this pathway, acetyl-CoA reacts with oxaloacetate to form citrate. ACAT1acetoacetyl-CoA thiolase, Ac-CoAacetyl-CoA, AcAc-CoAacetoacetyl-CoA, BDH-hydroxybutyrate dehydrogenase, bHB-hydroxybutyrate, CPT1carnitine palmitoyltransferase 1, HMGCLHMG-CoA lyase, HMGCS2HMG-CoA synthetase, MCT1monocarboxylate transporter 1, SCOTsuccinyl-CoA:3-ketocid-CoA transferase, TCAtricarboxylic acid cycle. FGF21 expression is in that case regulated not only by PPAR, but also by HDAC3-mediated repression. Ketogenesis and ketolysis (WP4742) - Homo sapiens - WikiPathways In such conditions, glucose is spared mainly for neurons, but also for erythrocytes and proliferating cells in bone marrow or those involved in tissue regeneration. Ketogenesis and ketolysis Apr. In opposition to these transcription factors, hepatocyte nuclear factor 4 (HNF4) represses Hmgcs2 transcription [28]. In the same way, Sirt3 also activates the enzymes involved in fatty acid oxidation, such as LCAD [29], which contributes to the activation of ketogenesis in the liver. The body is constantly producing small amounts of ketone bodies that can make 22 ATP each in normal circumstances, and it is regulated mainly by insulin. Disorders of Ketogenesis and Ketolysis - Oxford Academic Reflections on disadvantages of the use of free fatty acids as fuel for brain. Utilization of ketone bodies as a source of energy is a sign of metabolic flexibility, which is necessary for cell survival during fasting; however, ketone bodies also confer cytoprotection independent from their role in modulating energy potential. Youm Y.H., Nguyen K.Y., Grant R.W., Goldberg E.L., Bodogai M., Kim D., DAgostino D., Planavsky N., Lupfer C., Kanneganti T.D., et al. Ketogenesis is regulated in multiple stages, and a nuclear receptor peroxisome proliferator activated receptor (PPAR) is one of the key transcription factors taking part in this regulation. Ketogenesis - Wikipedia Their structures are shown in Figure 17.3. This highlights the importance in further understanding the complex roles of ketone bodies in modulating cellular signaling responses. Apart from acetylation, succinylation is the second type of HMGCS2 modification that takes place in mitochondria and profoundly influences HMGCS2 activity. Provision of peripheral tissues, such as skeletal muscle and heart, with ketone bodies as an alternative fuel for energy production results in glucose sparing for organs depending on glucose as an energy source. Owen O.E., Morgan A.P., Kemp H.G., Sullivan J.M., Herrera M.G., Cahill G.F., Jr. The first of these receptors was originally known as the nicotinic acid receptor, but has since be renamed the hydroxycarboxylic acid receptor 2 (HCAR2) in light of its ability to bind bHB. The neuroprotective potential of bHB led to formulation of KTX 0101, a bHB sodium salt, which has been clinically tested and used as a neuroprotectant for patients undergoing major surgical procedures, such as cardiopulmonary bypass [143]. Succinylation on either cysteine or on lysine residues usually represses enzymatic activities. This process uses fatty acids as fuel for all the body's tissues except RBCs (which are glucose-dependent) and the liver. Hyperketonemia and ketosis increase the risk of complications in type 1 Saraon P., Cretu D., Musrap N., Karagiannis G.S., Batruch I., Drabovich A.P., van der Kwast T., Mizokami A., Morrissey C., Jarvi K., et al. Quantitative proteomics reveals that enzymes of the ketogenic pathway are associated with prostate cancer progression.
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