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 Contentsâ€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦. iv List of Tablesâ€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦. viii List of Figuresâ€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦â€¦ ix Acknowledgementsâ€¦â€¦â€¦â€¦â€¦â€¦â Continue reading >>
Ketones are a beneficial product of fat metabolism in the body. When carbohydrate intake is restricted, it lowers blood sugar and insulin levels. As insulin levels fall and energy is needed, fatty acids flow from the fat cells into the bloodstream and are taken up by various cells and metabolized in a process called beta-oxidation. The end result of beta-oxidation is a molecule called acetyl-coA, and as more fatty acids are released and metabolized, acetyl-coA levels in the cells rise. This causes a sort of metabolic “feedback loop” which triggers liver cells to shunt excess acetyl-Coa into ketogenesis, or the making of ketone bodies. Once created, the liver dumps the ketone bodies into the blood stream and they are taken up by skeletal and heart muscle cells at rates of availability. In addition, the brain begins to use ketones as an alternate fuel when blood levels are high enough to cross the blood brain barrier. Testing Laboratory Microbiology - Air Quality - Mold Asbestos - Environmental - Lead emsl.com There are three major types of ketone bodies present in the human blood stream when the metabolic process of ketosis is dominant: Acetoacetate (AcAc) is created first β-hydroxybutyrate (BHB) is created from acetoacetate Acetone is a spontaneously created side product of acetoacetate In times of starvation, or a low carbohydrate intake resulting in low insulin levels, ketone bodies supply up to 50% of the energy requirements for most body tissues, and up to 70% of the energy required by the brain. Glucose is the main source of fuel for neurons when the diet is high in carbohydrates. But when carbs are restricted, ketogenesis becomes the primary fuel process for most cells. During fasting or low carbohydrate intake, levels of ketone bodies in the blood stream can Continue reading >>
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 >>
Ketone Bodies Metabolic Pathway (pw:0000069)
Description The ketone bodies metabolic pathway is used to convert acetyl-CoA formed in the liver into "ketone bodies": acetone, and more importantly acetoacetate and 3-hydroxybutyrate, which are transported in the blood to extrahepatic tissues where they are converted to acetyl-CoA and oxidized via the citrate cycle pathway for energy. The brain, which usually uses glucose for energy, can utilize ketone bodies under starvation conditions, when glucose is not available. When acetyl-CoA is not being metaboli...(more) Description: ENCODES a protein that exhibits 3-hydroxybutyrate dehydrogenase activity (ortholog); NAD binding (ortholog); oxidoreductase activity, acting on the CH-CH group of donors, NAD or NADP as acceptor (ortholog); INVOLVED IN epithelial cell differentiation (ortholog); fatty acid beta-oxidation (ortholog); heme metabolic process (ortholog); PARTICIPATES IN butanoate metabolic pathway; ketone bodies metabolic pathway; FOUND IN cytoplasm (ortholog); cytosol (ortholog); extracellular exosome (ortholog); INTERACTS WITH 2,3,7,8-tetrachlorodibenzodioxine; 2,4-dinitrotoluene; 2,6-dinitrotoluene Continue reading >>
Ketone Bodies Liver Mitochondria Have The Capacity To Convert Acetyl Coa Derived From Fatty Acid Oxidation Into Ketone Bodies Which Are: 1- Acetoacetic.
Presentation on theme: "Ketone bodies Liver mitochondria have the capacity to convert acetyl CoA derived from fatty acid oxidation into ketone bodies which are: 1- Acetoacetic."— Presentation transcript: 1 Ketone bodies Liver mitochondria have the capacity to convert acetyl CoA derived from fatty acid oxidation into ketone bodies which are: 1- Acetoacetic acid 2- β-hydroxy butyric acid 3- Acetone Functions of ketone bodies: 1-Used as source of energy. They are reconverted into acetyl CoA which is oxidized in Kreb's cycle to give energy. 2- In prolonged fasting and starvation, ketone bodies can be used as source of energy by most tissues except liver. N.B. In fasting, most tissues get energy from oxidation of both ketone bodies and fatty acids, but the brain gets its energy from oxidation of ketone bodies. Brain never oxidizes fatty acids. 2 Synthesis of ketone bodies by the liver (Ketogenesis) Site of ketogenesis: Mitochondria of liver cells due to high activity of HMG-CoA synthase, HMG- CoA- lyase. Steps of ketogenesis: See Figure (not required) 1- 3 molecules of acetyl CoA are condensed to give 3-hydroxy 3-glutaryl CoA (HMG CoA). This step is catalyzed by HMG CoA synthase (the key enzyme) 2- HMG CoA is then broken by HMG CoA lyase enzyme to acetoacetate. 3- Part of acetoacetate is converted into acetone and part is converted into β-hydroxy butyric acid Notes on ketogenesis: 1- HMG- CoA synthase is the rate limiting enzyme in the synthesis of ketone bodies and is present in significant amounts only in the liver. 3- Acetone is a volatile, nonmetabolized product that can be released in the breath. 3 Regulation of ketogenesis: Regulation of HMG-CoA synthase A- Inhibited after CHO diet (after meal): CHO diet inhibits HMG-CoA synthase. In addition, after meal, insulin i Continue reading >>
Gs L36 Liver Metabolism-fasting Fat Oxidation & Ketogenesis
Start Quiz! brain, erythrocytes, and adrenal medulla, cannot use fatty acids for energy fatty acids must first be released from triacylglycerols which are stored in adipose tissue, a process called lipolysis whenever the concentration of FA's increases in the blood which occurs normally between meals (fasted state) and also during periods of prolonged fasting or starvation the mitochondria matrix acetyl CoA and NADH/ FADH2 products which enter the TCA cycle and electron transport chain, respectively, thus generating significant amounts of ATP liver is unable to oxidize the ketone bodies it synthesizes, so they are exported into the blood and delivered primarily to the brain ketone bodies can not only supply energy to the brain in periods of long fasting but it can spare muscle protein which would have been degraded for gluconeogenesis Continue reading >>
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We Really Can Make Glucose From Fatty Acids After All! O Textbook, How Thy Biochemistry Hast Deceived Me!
Biochemistry textbooks generally tell us that we can’t turn fatty acids into glucose. For example, on page 634 of the 2006 and 2008 editions of Biochemistry by Berg, Tymoczko, and Stryer, we find the following: Animals Cannot Convert Fatty Acids to Glucose It is important to note that animals are unable to effect the net synthesis of glucose from fatty acids. Specficially, acetyl CoA cannot be converted into pyruvate or oxaloacetate in animals. In fact this is so important that it should be written in italics and have its own bold heading! But it’s not quite right. Making glucose from fatty acids is low-paying work. It’s not the type of alchemy that would allow us to build imperial palaces out of sugar cubes or offer hourly sweet sacrifices upon the altar of the glorious god of glucose (God forbid!). But it can be done, and it’ll help pay the bills when times are tight. All Aboard the Acetyl CoA! When we’re running primarily on fatty acids, our livers break the bulk of these fatty acids down into two-carbon units called acetate. When acetate hangs out all by its lonesome like it does in a bottle of vinegar, it’s called acetic acid and it gives vinegar its characteristic smell. Our livers aren’t bottles of vinegar, however, and they do things a bit differently. They have a little shuttle called coenzyme A, or “CoA” for short, that carries acetate wherever it needs to go. When the acetate passenger is loaded onto the CoA shuttle, we refer to the whole shebang as acetyl CoA. As acetyl CoA moves its caboose along the biochemical railway, it eventually reaches a crossroads where it has to decide whether to enter the Land of Ketogenesis or traverse the TCA cycle. The Land of Ketogenesis is a quite magical place to which we’ll return in a few moments, but n Continue reading >>
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Reactions and Metabolic Pathways A progression of metabolic reactions from beginning to end is called a pathway Intermediates of reactions Anabolic pathways Catabolic pathways Energy for the cell Energy used in cells come from the chemical bonds found between atoms in carbohydrate, fat, protein, and alcohol Most energy is from the sun and involved in reactions converting carbon dioxide and water into glucose – (photosynthesis) Glucose used in cell respiration to produce ATP used by all reactions in all cells Types of energy: chemical, mechanical, electrical, osmotic Oxidation-Reduction Reactions A substance is oxidized when it loses one or more electrons A substance is reduced when it gains one or more electrons Oxidation-reduction reactions are controlled by enzymes Antioxidants – compounds that donate electrons to oxidized compounds, putting them into a more reduced (stable) state Oxidized compounds tend to be highly reactive Vitamins E and C are antioxidants Remember phytochemicals! Glycolysis, Citric Acid Cycle (also called Krebs Cycle), and Electron Transport Chain (ETC) Glycolysis Occurs in the cytosol of the cell Begin process with glucose 2 ATP used 4 ATP produced = 2 ATP net Water molecule is removed Hydrogen atoms removed from intermediates by NAD molecules 2 pyruvate molecules produced at end of the pathway If no oxygen present in the cell then pyruvates are converted into lactate – this process is called anaerobic respiration Intermediate step: Pyruvate to Acetyl CoA (occurs in the mitochodria) Citric Acid Cycle Occurs in the mitochondria Acetyl CoA added to compound in the cycle Hydrogens are removed by NAD molecules and FAD molecules Carbon dioxide is removed from intermediates GTP produced (a usable energy source like ATP) Electron Transport Chain H Continue reading >>
What is Ketogenesis? Ketogenesis (1, 2) is a biochemical process that produces ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies the needed energy of certain organs, especially the brain. Not having enough ketogenesis could result to hypoglycaemia and over production of ketone bodies leading to a condition called ketoacidosis. It releases ketones when fat is broken down for energy. There are many ways to release ketones such as through urination and exhaling acetone. Ketones have sweet smell on the breath. (3) Ketogenesis and ketoacidosis are entirely different thing. Ketoacidosis is associated with diabetes and alcoholism, which could lead to even serious condition like kidney failure and even death. Picture 1 : Ketogenic pathway Photo Source : medchrome.com Image 2 : A pyramid of ketogenic diet Photo Source : www.healthline.com What are Ketone bodies? Ketone bodies are water soluble molecules produced by the liver from fatty acids during low food intake or fasting. They are also formed when the body experienced starvation, carbohydrate restrictive diet, and prolonged intense exercises. It is also possible in people with diabetes mellitus type 1. The ketone bodies are picked up by the extra hepatic tissues and will convert to acetyl-CoA. They will enter the citric acid cycle and oxidized in the mitochondria to be used as energy. Ketone bodies are needed by the brain to convert acetyl-coA into long chain fatty acids. Ketone bodies are produced in the absence of glucose. (1, 2, 3) It is easy to detect the presence of ketone bodies. Just observe the person’s breath. The smell of the breath is fruity and sometimes described as a nail polish remover-like. It depicts the presence of acetone or ethyl acetate. The ketone bodies includ Continue reading >>
Chapter 14: Multiple Choice Questions
Instructions Answer the following questions and then press 'Submit' to get your score. Which of the following statements about triacylglycerols is correct? Which of the following statements about fatty acids is correct? Which of the following statements about the activation of fatty acids is correct? Which of the following statements about -oxidation of fatty acids is correct? Which of the following statements about the ketone body acetoacetate is not true? What would be the consequences of inhibiting the carnitine shuttle which transports fatty acids into the mitochondria? The liver synthesizes ketone bodies e.g. acetoacetate and hydroxybutyrate in fasting and starvation but cannot utilize them. Why is that? Which of the following statements about the oxidation of fatty acids is correct? Which of the following statements about the transport of fatty acyl-CoA derivatives (activated fatty acids) into the mitochondria is correct? Which of the following statements about the ketone bodies, acetoacetate and -hydroxybutyrate is correct? Continue reading >>
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Tributes To Energy Production By Entering Glycolysis As Dihydroxyacetone Phosphate.
25.6 The Key Intermediate-Acetyl CoA 77t 25.6 The key intermediote-acetyl CoA AIMS: To name the shored intermediote of both carbohydrote ond fotty ocid metobolism, To list four fotes of ocetyl CoA in the liver. Now that we have seen how the body oxidizes fatty acids, we can form an overall picture of the various parts of fatty acid metabolism. We can exam- ine the relationships between carbohydrate metabolism and fatty acid metabolism at the same time. Since the liver conducts more carbohydrate metabolism and fatty acid metabolism than any other organ, this discus- sion will focus on it. Figure 25.4 shows the relationships we will be examining in the remain- der of this chapter. Refer to it often as you read on. The figure shows that Focus Fatty acid metabolism and carbohydrate metabolism intersect at acetyl CoA. Figure 25.4 The major pathways of lipid metab- olism in the liver and their relation- ship to carbohydrate metabolism. Converting carbohydrates to fatty acids is an efficient way to store energy. fatty acids entering the liver from the blood may be reslmthesized into triglycerides and stored in the adipose tissue there. Alternatively, fatty acids may be broken do',nm to aceryl CoA. Glucose is also broken do',nm to acetyl CoA. If you are beginning to suspect that aceryl CoA must be a key com- pound in the metabolic interplay between carbohydrate and fatty acid metabolism, you are certainly correct. Four possible fates await the acetyl CoA produced from fatty acids or glucose in the liver: 1. The acetyl CoA in the mitochondria may be oxidized to carbon dioxide and water in the citric acid cycle and respiration. This pathway, which is used if the liver cells need to generate energy through respiration, makes it clear that the citric acid cycle is shared by both gl Continue reading >>
What Is Anabolism?
Anabolism is the process by which the body utilizes the energy released by catabolism to synthesize complex molecules. These complex molecules are then utilized to form cellular structures that are formed from small and simple precursors that act as building blocks. Stages of anabolism There are three basic stages of anabolism. Stage 1 involves production of precursors such as amino acids, monosaccharides, isoprenoids and nucleotides. Stage 2 involves activation of these precursors into reactive forms using energy from ATP Stage 3 involves the assembly of these precursors into complex molecules such as proteins, polysaccharides, lipids and nucleic acids. Sources of energy for anabolic processes Different species of organisms depend on different sources of energy. Autotrophs such as plants can construct the complex organic molecules in cells such as polysaccharides and proteins from simple molecules like carbon dioxide and water using sunlight as energy. Heterotrophs, on the other hand, require a source of more complex substances, such as monosaccharides and amino acids, to produce these complex molecules. Photoautotrophs and photoheterotrophs obtain energy from light while chemoautotrophs and chemoheterotrophs obtain energy from inorganic oxidation reactions. Anabolism of carbohydrates In these steps simple organic acids can be converted into monosaccharides such as glucose and then used to assemble polysaccharides such as starch. Glucose is made from pyruvate, lactate, glycerol, glycerate 3-phosphate and amino acids and the process is called gluconeogenesis. Gluconeogenesis converts pyruvate to glucose-6-phosphate through a series of intermediates, many of which are shared with glycolysis. Usually fatty acids stored as adipose tissues cannot be converted to glucose thr Continue reading >>
Definition: Acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main use is to convey the carbon atoms within the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for energy production. Its is the base of the biosynthesis of fatty acids and cholesterol. Acetyl-CoA is also an important component in the biogenic synthesis of the neurotransmitter acetylcholine. Choline, in combination with Acetyl-CoA, is catalyzed by the enzyme choline acetyltransferase to produce acetylcholine and a coenzyme a byproduct. Structure In chemical structure, acetyl-CoA is the thioester between coenzyme A (a thiol) and acetic acid (an acyl group carrier). Acetyl-CoA is produced during the second step of aerobic cellular respiration, pyruvate decarboxylation, which occurs in the matrix of the mitochondria. Acetyl-CoA then enters the citric acid cycle (Krebs cycle). Metabolism Acetyl-CoA is produced in mitochondria through the metabolism of fatty acids and the oxidation of pyruvate to acetyl-CoA. When ATP is needed, this acetyl-CoA can enter the Krebs cycle to drive oxidative phosphorylation. When ATP supplies are abundant, the acetyl-CoA can be diverted to other purposes like energy storage in the form of fatty acids. The biosynthesis of fatty acids from this acetyl-CoA cannot take place directly however, since it is produced inside mitochondria while fatty acid biosynthesis occurs in the cytosol. There is not a mechanism that directly transports acetyl-CoA out of mitochondria. To be transported, the acetyl-CoA must be chemically converted to citric acid using a pathway called the tricarboxylate transport system. Inside mitochondria, the enzyme citrate synthase joins acetyl-CoA with oxaloacetate to make citrate. This citrate is transported Continue reading >>
Chapter 25: Lipids: Lipolysis, Fatty Acid Oxidation, And Ketogenesis
Chapter 25: Lipids: Lipolysis, Fatty Acid Oxidation, and Ketogenesis Parents of a 3-month-old infant arrive at the ER agitated and frightened by the extreme lethargy and near comatose state of their child. Examination shows the infant to be severely hypoglycemic accompanied by low measurable ketones in the urine and blood. Blood analysis also indicates an elevation in butyric and propionic acids and as well as C8-acylcarnitines. A deficiency in which of the following enzymes is most likely responsible for these observations? B. hormone-sensitive lipase (HSL) C. lipoprotein lipase (LPL) D. long-chain acyl-CoA dehydrogenase (LCAD) E. medium-chain acyl-CoA dehydrogenase (MCAD) Answer E: In infants, the supply of glycogen lasts less than 6 hours and gluconeogenesis is not sufficient to maintain adequate blood glucose levels. Normally, during periods of fasting (in particular during the night) the oxidation of fatty acids provides the necessary ATP to fuel hepatic gluconeogenesis as well as ketone bodies for nonhepatic tissue energy production. In patients with MCAD deficiency there is a drastically reduced capacity to oxidize fatty acids. This leads to an increase in glucose usage with concomitant hypoglycemia. The deficit in the energy production from fatty acid oxidation, necessary for the liver to use other carbon sources, such as glycerol and amino acids, for gluconeogenesis further exacerbates the hypoglycemia. Normally, hypoglycemia is accompanied by an increase in ketone formation from the increased oxidation of fatty acids. In MCAD deficiency there is a reduced level of fatty acid oxidation, hence near-normal levels of ketones are detected in the serum. Oxidation of fatty acids requires the input of energy in the form of ATP. Which of the following enzyme activities Continue reading >>
6.9: Ketone Body Synthesis
In ketone body synthesis, an acetyl-CoA is split off from HMG-CoA, yielding acetoacetate, a four carbon ketone body that is somewhat unstable, chemically. It will decarboxylate spontaneously to some extent to yield acetone. Ketone bodies are made when the blood levels of glucose fall very low. Ketone bodies can be converted to acetyl-CoA, which can be used for ATP synthesis via the citric acid cycle. People who are very hypoglycemic (including some diabetics) will produce ketone bodies and these are often first detected by the smell of acetone on their breath. Figure 6.9.1: Ketone Body Reactions Acetone is of virtually no use for energy production since it is not readily converted to acetyl-CoA. Consequently, cells convert acetoacetate into beta- hydroxybutyrate, which is more chemically stable. Though technically not a ketone, beta-hydroxybutyrate is frequently referred to as a ketone body. Upon arrival at a target cell, it can be oxidized back to acetoacetate with conversion to acetyl-CoA. Both acetoacetate and beta-hydroxybutyrate can cross the blood-brain barrier and provide important energy for the brain when glucose is limiting. Continue reading >>