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What Is The Responsible Mechanism For The Formation Of Ketone Bodies?

Ketone Bodies

Ketone Bodies

Sort Ketone Bodies -->Represent 3 molecules that are formed when excess acetyl CoA cannot enter the TCA Cycle -->Represents 3 major molecules: 1)Acetoacetate 2)β-Hydroxybutyrate 3)Acetone -->Normal people produces ketones at a low rate -->Are only formed in the **LIVER**(by liver mitochondria) Reactions that lead to the formation of ketone bodies (***See pwrpt***) 1)2 Acetyl CoA molecules condense to form ***Acetoacetyl-CoA -->Is catalyzed by THIOLASE -->Represent the oppostie of thiolysis step in the oxidation of fatty acids -->Represent the parent compound of the 3 ketone bodies (2)Acetoacetyl CoA then reacts with another mol. of acetyl CoA to form **HMG-CoA* (3-hydroxy-3-methylglutaryl CoA) & *CoA** -->Reaction is catalyzed by **HMG-CoA Synthetase** -->HMG-CoA has 2 fates (can either progress to form ketone bodies OR can enter the pathway of CHOLESTEROL synthesis) -->Represent the **RATE-LIMITING STEP** in the synthesis of ketone bodies (3)HMG-CoA is cleaved to form **Acetoacetate**(First major ketone; represent ~20% of ketones) & another mol. of acetyl CoA -->Catalyzed by **HMG-CoA Lyase** (4) Acetoacetae can lead to the formation of β-hydroxybutyrate (~78% of ketone bodies) & Acetone (~2% of ketone bodies) via 2 separte reactions Interrelationships of the ketone bodies from Acetoacetate (1)Formation of β-hydroxybutyrate -->Acetoacetate will be reduced to form β-hyroxybutyrate in the mitochondrial matrix of the liver cell -->Is a REVERSIBLE RXN. -->Requires 1 mol of NADH (***Dependent on the NADH/NAD ratio inside the mitochondria) -->Catalyzed by β-hydroxybutyrate dehydrogenase (2)Formation of Acetone -->A slower, **spontaneous** decarboxylation to acetone -->In **DIABETIC KETOACIDOSIS, acetone imparts a characteristic smell to the patient's breath Features of Continue reading >>

Triacylglycerol Metabolism

Triacylglycerol Metabolism

Various types of lipids occur in the human body, namely This chapter will focus on triacylglycerol; cholesterol will be covered in a separate chapter. The metabolism of polar lipids will not be covered systematically. In contrast to polar lipids and cholesterol, which are found in the membranes of every cell, triacylglycerol is concentrated mostly in adipose (fat) tissue; minor amounts of triacylglycerol occur in other cell types, such as liver epithelia and skeletal muscle fibers. Yet, overall, triacylglycerol is the most abundant lipid species, and the only one with an important role in energy metabolism. Triacylglycerol occurs in human metabolism in two roles, namely1)as a foodstuff, which accounts for a significant fraction of our caloric intake, and 2)as a store of metabolic energy. This store can be replenished using dietary triacylglycerol or through endogenous synthesis from carbohydrates or proteins. The amount of energy stored per gram of tissue is far higher in fat than in any other tissue, for two reasons: 1.One gram of triacylglycerol itself contains more than twice as many calories as one gram of carbohydrates or protein. This is simply because triacylglycerol contains much less oxygen than carbohydrates, in which oxygen contributes half the mass but essentially no metabolic energy. Similarly, the oxygen, nitrogen and sulfur contained in protein detract from its energy density. 2.Triacylglycerol in fat cells coalesces to droplets that are entirely free of water. In contrast, protein and carbohydrates, including glycogen, always remain hydrated, which further diminishes the density of energy storage. Because of its high energy density, it makes sense that most of the excess glucose or protein is converted to fat, while only a limited fraction is stored as g Continue reading >>

Ketone Bodies As Signaling Metabolites

Ketone Bodies As Signaling Metabolites

Outline of ketone body metabolism and regulation. The key irreversible step in ketogenesis is synthesis of 3-hydroxy-3-methylglutaryl-CoA by HMGCS2. Conversely, the rate limiting step in ketolysis is conversion of acetoacetate to acetoacetyl-CoA by OXCT1. HMGCS2 transcription is heavily regulated by FOXA2, mTOR, PPARα, and FGF21. HMGCS2 activity is post-translationally regulated by succinylation and acetylation/SIRT3 deacetylation. Other enzymes are regulated by cofactor availability (e.g., NAD/NADH2 ratio for BDH1). All enzymes involved in ketogenesis are acetylated and contain SIRT3 deacetylation targets, but the functional significance of this is unclear other than for HMGCS2. Although ketone bodies are thought to diffuse across most plasma membranes, the transporter SLC16A6 may be required for liver export, whereas several monocarboxylic acid transporters assist with transport across the blood–brain barrier. Abbreviations: BDH1, β-hydroxybutyrate dehydrogenase; FGF21, fibroblast growth factor 21; FOXA2, forkhead box A2; HMGCS2, 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase 2; HMGCL, HMG-CoA lyase; MCT1/2, monocarboxylic acid transporters 1/2; mTOR, mechanistic target of rapamycin; OXCT1, succinyl-CoA:3-ketoacid coenzyme A transferase; PPARα, peroxisome proliferator-activated receptor α; SIRT3, sirtuin 3; SLC16A6, solute carrier family 16 (monocarboxylic acid transporter), member 6; TCA cycle, tricarboxylic acid cycle. 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 >>

Ketone Bodies Mimic The Life Span Extending Properties Of Caloric Restriction

Ketone Bodies Mimic The Life Span Extending Properties Of Caloric Restriction

The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway. Decreased IIS diminishes phosphatidylinositol (3,4,5) triphosphate (PIP3) production, leading to reduced PI3K and AKT kinase activity and decreased forkhead box O transcription factor (FOXO) phosphorylation, allowing FOXO proteins to remain in the nucleus. In the nucleus, FOXO proteins increase the transcription of genes encoding antioxidant enzymes, including superoxide dismutase 2, catalase, glutathione peroxidase, and hundreds of other genes. An effective method for combating free radical damage occurs through the metabolism of ketone bodies, ketosis being the characteristic physiological change brought about by caloric restriction from fruit flies to primates. A dietary ketone ester also decreases circulating glucose and insulin leading to decreased IIS. The ketone body, d-β-hydroxybutyrate (d-βHB), is a natural inhibitor of class I and IIa histone deacetylases that repress transcription of the FOXO3a gene. Therefore, ketosis results in transcription of the enzymes of the antioxidant pathways. In addition, the metabolism of ketone bodies results in a more negative redox potential of the NADP antioxidant system, which is a terminal destructor of oxygen free radicals. Addition of d-βHB to cultures of C. elegans extends life span. We hypothesize that increasing t Continue reading >>

Ketone Bodies

Ketone Bodies

Ketone bodies Acetone Acetoacetic acid (R)-beta-Hydroxybutyric acid Ketone bodies are three water-soluble molecules (acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone) that are produced by the liver from fatty acids[1] during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, prolonged intense exercise,[2], alcoholism or in untreated (or inadequately treated) type 1 diabetes mellitus. These ketone bodies are readily picked up by the extra-hepatic tissues, and converted into acetyl-CoA which then enters the citric acid cycle and is oxidized in the mitochondria for energy.[3] In the brain, ketone bodies are also used to make acetyl-CoA into long-chain fatty acids. Ketone bodies are produced by the liver under the circumstances listed above (i.e. fasting, starving, low carbohydrate diets, prolonged exercise and untreated type 1 diabetes mellitus) as a result of intense gluconeogenesis, which is the production of glucose from non-carbohydrate sources (not including fatty acids).[1] They are therefore always released into the blood by the liver together with newly produced glucose, after the liver glycogen stores have been depleted (these glycogen stores are depleted after only 24 hours of fasting)[1]. When two acetyl-CoA molecules lose their -CoAs, (or Co-enzyme A groups) they can form a (covalent) dimer called acetoacetate. Beta-hydroxybutyrate is a reduced form of acetoacetate, in which the ketone group is converted into an alcohol (or hydroxyl) group (see illustration on the right). Both are 4-carbon molecules, that can readily be converted back into acetyl-CoA by most tissues of the body, with the notable exception of the liver. Acetone is the decarboxylated form of acetoacetate which cannot be converted Continue reading >>

Ketone Body Synthesis

Ketone Body Synthesis

Types of Ketone Bodies and Their Function There are three substances in our body that are considered ketone bodies: Acetoacetate is a metabolic product of the liver. It can be converted into acetone and beta-hydroxybutyrate. Acetone is a product of spontaneous decarboxylation of acetoacetate or via the action of acetoacetate decarboxylase. It is disposed of with the respiratory air or in the urine. Acetone does not have any function in our metabolism. Beta-hydroxybutyrate is not a ketone body strictly speaking. It is derived from acetoacetate via the action of D-beta hydroxy butyrate dehydrogenase. It is the most abundant ketone body. Acetoacetate and beta-hydroxybutyrate are only synthesized in the mitochondrial matrix of hepatocytes. Brain, myocardial and skeletal muscles all rely on the re-conversion of these substances in times of low glucose levelssince they can traverse membranes easily. Since the brain cannot use fatty acids for energy generation because the blood-brain barrier is not permeable to fatty acids, it is dependent on ketone bodies in periods of fasting as its sole energy resource. Using ketone bodies, the brain can reduce its glucose demand from an average of about 150g/day to about 50g/day.They are transported to the brain via monocarboxylate transporters 1 and 2. Activation of Ketone Body Synthesis From a biochemical perspective, ketone body synthesis will be reinforced whenever there is an increased presence of acetyl-CoA (the starting substance of ketone body synthesis), as is the case during longer periods of fasting or starvation. Furthermore, diabetes mellitus causes an accumulation of acetyl-CoA: the lower insulin production or higher insulin resistance leads to an increase in the degradation of fatty acids which, in turn, leads to more acetyl Continue reading >>

Fenofibrate Induces Ketone Body Production In Melanoma And Glioblastoma Cells

Fenofibrate Induces Ketone Body Production In Melanoma And Glioblastoma Cells

1Department of Food Biotechnology, Faculty of Food Technology, University of Agriculture, Krakow, Poland 2Molecular and Metabolic Oncology Program, Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA 3Department of Human Nutrition, Faculty of Food Technology, University of Agriculture, Krakow, Poland 4Neurological Cancer Research, Stanley S Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA Ketone bodies [beta-hydroxybutyrate (bHB) and acetoacetate] are mainly produced in the liver during prolonged fasting or starvation. bHB is a very efficient energy substrate for sustaining ATP production in peripheral tissues; importantly, its consumption is preferred over glucose. However, the majority of malignant cells, particularly cancer cells of neuroectodermal origin such as glioblastoma, are not able to use ketone bodies as a source of energy. Here, we report a novel observation that fenofibrate, a synthetic peroxisome proliferator-activated receptor alpha (PPARa) agonist, induces bHB production in melanoma and glioblastoma cells, as well as in neurospheres composed of non-transformed cells. Unexpectedly, this effect is not dependent on PPARa activity or its expression level. The fenofibrate-induced ketogenesis is accompanied by growth arrest and downregulation of transketolase, but the NADP/NADPH and GSH/GSSG ratios remain unaffected. Our results reveal a new, intriguing aspect of cancer cell biology and highlight the benefits of fenofibrate as a supplement to both canonical and dietary (ketogenic) therapeutic approaches against glioblastoma. Continue reading >>

Regulation Of Ketone Body And Coenzyme A

Regulation Of Ketone Body And Coenzyme A

METABOLISM IN LIVER by SHUANG DENG Submitted in partial fulfillment of the requirements For the Degree of Doctor of Philosophy Dissertation Adviser: Henri Brunengraber, M.D., Ph.D. Department of Nutrition CASE WESTERN RESERVE UNIVERSITY August, 2011 SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of __________________ ____________ _ _ candidate for the ________________________________degree *. (signed) ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. Shuang Deng (chair of the committee) Edith Lerner, PhD Colleen Croniger, PhD Henri Brunengraber, MD, PhD Doctor of Philosophy Janos Kerner, PhD Michelle Puchowicz, PhD Paul Ernsberger, PhD I dedicate this work to my parents, my son and my husband iv TABLE OF CONTENTS Table of Contents…………………………………………………………………. iv List of Tables………………………………………………………………………. viii List of Figures……………………………………………………………………… ix Acknowledgements………………â Continue reading >>

Exam 4

Exam 4

Study Questions 1. What are the two main regulated enzymes required for glycogen synthesis and glycogen breakdown? Briefly describe the mechanism(s) that control their activity. Glycogen synthase is the major enzyme required for glycogen synthesis. It is inhibited by phosphorylation. Glucagon, a hormone that signals low glucose levels, stimulates phosphorylation of glycogen synthase, and also promotes inactivation (by phosphorylation) of a protein phosphatase inhibitor, thus ensuring that glycogen synthase remains phosphorylated and inactive. Glycogen phosphorylase is the major enzyme required for glycogen breakdown and it is activated by glucagon through a phosphorylation regulatory mechanism. Bottom line: glucagon signaling inhibits glycogen synthase activity and stimulates glycogen phosphorylase activity - both by phosphorylation. 2a. Individuals with von Gierke's disease, which is a lack of glucose-6-phosphatase in the liver, accumulate large amounts of glycogen in the liver. Why? Glucose-6-P accumulates as a result of stimulated glycogen breakdown (glucagon signals low blood sugar), but because it can't leave the liver, Glu-6-P stimulates glycogen synthase. Moreover, Glu-6-P derived from gluconeogenesis (also stimulated by low blood sugar) is converted to glycogen by the same mechanism (simulation of glycogen synthase). Bottom line: high cellular levels of glucose-6-P stimulates glycogen synthesis. 2b. Why would individuals with von Gierke's disease release a small amount of glucose into the blood after injection with a high dose of glucagon? Glucagon stimulates glycogen breakdown, and the product of debranching enzyme is free glucose, which is released into the blood (~10% of available glucose in glycogen is contained in alpha-1,6 branch points). 3. What has a hig Continue reading >>

Ketone Bodies Formed In The Liver Are Exported To Other Organs

Ketone Bodies Formed In The Liver Are Exported To Other Organs

Ketone Bodies In human beings and most other mammals, acetyl-CoA formed in the liver during oxidation of fatty acids may enter the citric acid cycle (stage 2 of Fig. 16-7) or it may be converted to the "ketone bodies" acetoacetate, D-β-hydroxybutyrate, and acetone for export to other tissues. (The term "bodies" is a historical artifact; these compounds are soluble in blood and urine.) Acetone, produced in smaller quantities than the other ketone bodies, is exhaled. Acetoacetate and D-β-hydroxybutyrate are transported by the blood to the extrahepatic tissues, where they are oxidized via the citric acid cycle to provide much of the energy required by tissues such as skeletal and heart muscle and the renal cortex. The brain, which normally prefers glucose as a fuel, can adapt to the use of acetoacetate or D-β-hydroxybutyrate under starvation conditions, when glucose is unavailable. A major determinant of the pathway taken by acetyl-CoA in liver mitochondria is the availability of oxaloacetate to initiate entry of acetyl-CoA into the citric acid cycle. Under some circumstances (such as starvation) oxaloacetate is drawn out of the citric acid cycle for use in synthesizing glucose. When the oxaloacetate concentration is very low, little acetyl-CoA enters the cycle, and ketone body formation is favored. The production and export of ketone bodies from the liver to extrahepatic tissues allows continued oxidation of fatty acids in the liver when acetyl-CoA is not being oxidized via the citric acid cycle. Overproduction of ketone bodies can occur in conditions of severe starvation and in uncontrolled diabetes. The first step in formation of acetoacetate in the liver (Fig. 16-16) is the enzymatic condensation of two molecules of acetyl-CoA, catalyzed by thiolase; this is simply Continue reading >>

Aspects Of Ketogenesis: Control And Mechanism Of Ketone-body Formation In Isolated Rat-liver Mitochondria.

Aspects Of Ketogenesis: Control And Mechanism Of Ketone-body Formation In Isolated Rat-liver Mitochondria.

Abstract The synthesis of ketone bodies by intact isolated rat-liver mitochondria has been studied at varying rates of acetyl-CoA production and of acetyl-CoA utilization in the Krebs cycle. Factors which enhanced the rate of acetyl-CoA production caused an increase in the fraction of acetyl-CoA which was incorporated into ketone bodies. On the other hand, it was found that factors which stimulated the formation of citrate lowered the relative rate of ketogenesis. It is concluded that acetyl-CoA is preferentially used for citrate synthesis, if the level of oxaloacetate in the mitochondrial matrix space is adequate. The intramitochondrial level of oxaloacetate, which is determined by the malate concentration and the ratio of NADH over NAD+, is the main factor controlling the rate of citrate synthesis. The ATP/ADP ratio per se does not affect the activity of citrate synthase in this in vitro system. Ketogenesis can be described as an overflow of acetyl-groups: Ketone-body formation is stimulated only when the rate of acetyl-CoA production increases beyond the capacity for citrate synthesis. The interaction between fatty acid oxidation and pyruvate metabolism and the effects of long-chain acyl-CoA on mitochondrial metabolism are discussed. Ketone bodies which were generated during the oxidation of [1-14C] fatty acids were preferentially labelled in their carboxyl group. This carboxyl group had the same specific activity as the acetyl-CoA pool, whereas the specific activity of the acetone moiety of acetoacetate was much lower, especially at low rates of ketone-body formation. The activities of acetoacetyl-CoA deacylase and the hydroxymethylglutaryl-CoA (HMG-CoA) pathway were compared in soluble and mitochondrial fractions of rat- and cow-liver in different ketotic states. I 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 >>

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