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Ketogenesis

No Net Synthesis

No Net Synthesis

·Standard AAs are degraded to one of 7 metabolic intermediates: pyruvate; a-ketoglutarate; succinyl-CoA; fumarate; oxaloacetate; acetyl-CoA; or acetoacetate. ·In animals, Leucine and Lysine are the only two purely ketogenic AAs (i.e. they can be converted to acetoacetate or acetyl-CoA; no net synthesis of pyruvate or any of the TCA intermediates). ·Five AAs (Isoleucine; Threonine; Phenylalanine; Tyrosine; Tryptophan) are both glucogenic (i.e. they are first converted to pyruvate or any of the TCA intermediates) and ketogenic. ·13 other AAs are purely glucogenic. (Chapter 19, section 3, pp. 649-650. Fig. 19-21) ·A mitochondrial process by which acetyl-CoA is converted to acetoacetate and D-β-hydroxybutyrate. ·Ketone Bodies: acetoacetate, D-β-hydroxybutyrate, and acetone. ·Ketone bodies are water-soluble equivalents of fatty acids. ·Important metabolic fuels for peripheral tissues, especially heart and skeletal muscle. ·The brain utilizes glucose for energy under normal circumstances. However, ketone bodies become brain’s major fuel source during starvation. A. Formation of Acetoacetate in Mitochondria ·Thiolase ·Hydroxymethylglutaryl-CoA synthaseb-Hydroxymethylglutaryl-CoA (Corresponding enzymes also exist in cytosol which, together with HMG-CoA reductase, function in mevalonate synthesis.) ·HMG-CoA Lyase B. Formation of D-β-Hydroxybutyrate ·β-Hydroxybutyrate Dehydrogenase Note: enoyl-CoA hydratase 3-L-hydroxyacyl-CoA DH trans-∆2-enoyl-CoA→L-β-hydroxyacyl-CoA→β-ketoacyl-CoA β-ketoacyl-ACP→D- β-hydroxyacyl-ACP→trans-∆2-enoyl-ACP C. Formation of Acetone (by a facile nonenzymatic reaction) ======================================================= Utilization of Ketone Bodies (Fig. 19-22) Liver releases acetoacetate and β-hydroxybutyrate → Continue reading >>

Ketogenesis

Ketogenesis

L-(+)-Β-Hydroxybutyrate Although hepatic ketogenesis produces only d-(–)-βOHB, the physiologic substrate used for oxidation, L-(+)-βOHB is measurable in ketolytic tissues but not in the circulation. L-(+)-βOHB is generated from the hydrolysis of the β-oxidation intermediate L-(+)-βOHB-CoA but is not a BDH1 substrate.153-156 SLC16A transporters in rat myocytes do not demonstrate stereoselectivity for βOHB.157 In brains of suckling rats, L-(+)-βOHB can be used for synthesis of fatty acids and sterols.91,92 These observations may be important when racemic dl-βOHB is administered to humans or used for experiments. Stop Ketoacids Production Insulin plays a central role in arresting ketogenesis; there may be, however, a lag period of a few hours before there is an appreciable decline in the rate of production of ketoacids. This is usually not an urgent aspect of therapy because, based on data from adult subjects with starvation ketosis, the maximum rate of hepatic production of ketoacids is about 1 mmol/min. Hence, the administration of insulin can be delayed if required, as in the case of a patient with DKA and an initial PK of less than 4 mmol/L (see the following discussion). In our view, the only circumstance in which insulin must be administered urgently in a patient with DKA is the presence of ECG changes related to hyperkalemia because of its effect to induce a shift of K+ ions into cells. The effects of insulin to treat hyperglycemia are minimal early in therapy. Rather, the PGlucose will fall initially as a result of re-expansion of the ECF volume (dilution) and glucosuria caused by the rise in GFR. Six to eight hours after therapy begins, insulin will lower PGlucose by increasing the rate of oxidation of glucose because competing fat fuels are no longer a Continue reading >>

Mastering Nutrition Episode 22: Ketogenesis Isn’t All About Carbs And Insulin

Mastering Nutrition Episode 22: Ketogenesis Isn’t All About Carbs And Insulin

Did you know that adding MCT oil to your pasta is more ketogenic than restricting your carbohydrates to ten percent of calories? Many people think of carbohydrate and insulin as central to ketogenesis, but the direct biochemical event that initiates ketone formation is actually the oversupply of acetyl groups to the TCA cycle during conditions of oxaloacetate depletion. While largely a biochemistry lesson, in this episode I also teach you the practical implications of this. There is more than one route to ketogenesis, and while they all produce ketones, they are fundamentally different in important ways. Adding coconut, MCT oil, or exogenous ketones allows you to reap benefits of ketones without necessarily restricting carbohydrates and insulin, and that may be useful if you are also trying to reap some of the benefits of carbohydrate and insulin. On the other hand, certain conditions that respond to ketogenic diets, for example refractory childhood epilepsy, need stronger degrees of ketogenesis than you can achieve simply by adding MCT oil to pasta. Understanding the difference allows you to better make practical decisions about your diet that are most consistent with your priorities. Listen on ITunes or Stitcher. Click here to stream. Right-click (control-click on the Mac) here and choose “save as” (“save link as” on Mac) to download. Subscribe in your own reader using this RSS feed. Or, watch the YouTube video: In this episode, you’ll find all of the following and more (these times refer to the podcast, and they may be different in the YouTube video): 01.00 An announcement about the paleo event I am speaking at in Brooklyn on August 9th. 03:17 The cliff notes. 04:55 The Snapchat discussion that inspired this episode. 05:44 Why the idea that protein suppress Continue reading >>

Substrate And Hormonal Regulation Of Ketogenesis In Vivo

Substrate And Hormonal Regulation Of Ketogenesis In Vivo

Research project Description The proposed research will continue our work in the area of substrate and hormonal regulation of ketogenesis in vivo. Previous isotope dilution studies of ketone body metabolism have used a 14C ketone body tracer, and have utilized so-called "total ketone body specific activity" because of in vitro isotopic non-equilibration between the major ketone body pools (acetoacetate and Beta-hydroxybutyrate); however, the validity of this approach has recently been questioned. A number of in vitro studies have suggested that a variety of intermediary metabolites may be involved in non-hormonal regulation of ketogenesis; this concept, however, has not been systematically examined in vivo. We have recently developed a method for the determination of stable isotopic enrichment in ketone bodies using gas chromatography/mass spectroscopy. In the proposed studies, [3-14C] Beta-hydroxybutyrate and [3,4-13C2] acetoacetate are used in a dual isotope modeling technique to determine whole body rates of appearance, disappearance, and interconversion of ketone bodies. The proposal will focus initially on validation of the dual isotope model and subsequently on potential substrate factors involved in the regulation of ketogenesis. Specifically, these studies will: 1) determine which isotope model (the dual isotope technique versus "total ketone body specific activity" best predicts inflow of ketone bodies from an exogenous infusion, and subsequently compare these isotope dilution methods with endogenous ketone, and subsequently compare these isotope dilution methods with endogenous ketone body production determined directly by portal and hepatic venous catheterization in fed, fasted, and diabetic dogs; 2) determine whether physiologic increases in Cori and tricarb Continue reading >>

Ketogenesis & Ketolysis

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 >>

Chapter 22. Oxidation Of Fatty Acids: Ketogenesis

Chapter 22. Oxidation Of Fatty Acids: Ketogenesis

After studying this chapter, you should be able to: Describe the processes by which fatty acids are transported in the blood and activated and transported into the matrix of the mitochondria for breakdown to obtain energy. Outline the β-oxidation pathway by which fatty acids are metabolized to acetyl-CoA and explain how this leads to the production of large quantities of ATP from the reducing equivalents produced during β-oxidation and further metabolism of the acetyl-CoA via the citric acid cycle. Identify the three compounds termed “ketone bodies” and describe the reactions by which they are formed in liver mitochondria. Appreciate that ketone bodies are important fuels for extrahepatic tissues and indicate the conditions in which their synthesis and use are favored. Indicate the three stages in the metabolism of fatty acids where ketogenesis is regulated. Understand that overproduction of ketone bodies leads to ketosis and, if prolonged, ketoacidosis, and identify pathological conditions when this occurs. Give examples of diseases associated with impaired fatty acid oxidation. Although fatty acids are broken down by oxidation to acetyl-CoA and also synthesized from acetyl-CoA, fatty acid oxidation is not the simple reverse of fatty acid biosynthesis but an entirely different process taking place in a separate compartment of the cell. The separation of fatty acid oxidation in mitochondria from biosynthesis in the cytosol allows each process to be individually controlled and integrated with tissue requirements. Each step in fatty acid oxidation involves acyl-CoA derivatives, is catalyzed by separate enzymes, utilizes NAD+ and FAD as coenzymes, and generates ATP. It is an aerobic process, requiring the presence of oxygen. Increased fatty acid oxidation is a charac 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 >>

Ketogenesis

Ketogenesis

1. By Dr. Inayat ur Rahman Abbasi MBBS, M.Phil Biochemistry Associate Professor of Biochemistry Azad Jammu & Kashmir Medical College Muzaffarabad 2.  There are three important compounds in the body which are collectively called ketone bodies or acetone bodies or incorrectly ketones, Because all ketones are not KB and all KB are not chemically ketones. Dr. Inayat u Rahman Abbasi 2 3.  These are Aceto-acetate (primary KB), Acetone & β-Hydroxy Butyrate (secondary KB). Ketogenesis starts from mitochondrial Acetyl CoA in Liver, synthesis is mainly hepatic in nature but liver due to absence of enzyme thiophrase or Aceto-acety CoA transferase is unable to utilized KB as source of energy. So KB’s synthesis is hepatic but their utilization is extra-hepatic in nature. Dr. Inayat u Rahman Abbasi 3 4.  These are the source of energy (when needed) especially for cardiac, skeletal muscles, brain and adrenal cortex. These are soluble in aquous solution, so in plasma these are transported as such and do not required any lipoproteins. Dr. Inayat u Rahman Abbasi 4 5.  Ketogenesis and their utilization is taking place even in normal conditions but both process occur at slow level in such a way that their normal level remains <1.0 mg/dl. Dr. Inayat u Rahman Abbasi 5 6.  KB concentration when increased in body indicates: Excessive production acetyl CoA (increased Lipolysis) or Depressed utilization of acetyl CoA by TCA-Cycle. Main causes are uncontrolled Diabetes, starvation, prolonged fasting, excessive diarrhea/ vomiting. Dr. Inayat u Rahman Abbasi 6 7.  Ketone bodies (being an acid) when increased in plasma, liberate H+ ions, which are buffered by HCO3-/H2CO3 buffere system. But if their production is high, buffer will fail leading to high concen Continue reading >>

Ketogenesis

Ketogenesis

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 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] Ketogenesis takes place in the setting of low glucose levels in the blood, after exhaustion of other cellular carbohydrate stores, such as glycogen. It can also take place when there is insufficient insulin (e.g. in 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 amounts of intermediates such as oxaloacetate, acetyl-CoA is then used instead in biosynthesis of ketone bodies via acetoacyl-CoA and β-hydroxy-β-methylglutaryl-CoA (HMG-CoA). Deaminated amino acids that are ketogenic, such as leucine, also feed TCA cycle, forming acetoacetate & ACoA and thereby produce ketones.[1] Besides its Continue reading >>

A Link Between Mechanisms Of Calorie Restriction And Ketogenesis

A Link Between Mechanisms Of Calorie Restriction And Ketogenesis

Calorie restriction slows aging in most species and lineages tested to date, though the size of the effect on life span diminishes as species life span increases. Calorie restriction produces very similar short-term health benefits in humans and mice, but mice live as much as 40% longer as a result. We certainly do not. The necessary human studies have yet to run, but the consensus in the research community is that five years of additional life expectancy for calorie restricted humans is about as much as could be expected. The beneficial response to calorie restriction isn't just one mechanism under the hood, though increased autophagy appears to be an outsized contribution. Calorie restriction changes just about everything there is to be measured in cellular metabolism, shifting the behavior of many networks of linked genes and protein interactions. Given these networks, there are a range of other means of provoking some of the same effects. This is true for most aspects of cellular biochemistry: there is never only one way to produce change. Among the alternative means to touch on some of the changes involved in calorie restriction are intermittent fasting without calorie deficit, protein restriction, such as low methionine diets, and carbohydrate restriction - the much-hyped ketogenic diet, which is the topic for today. All structured popular diets are much-hyped, of course, surrounded by a moat of nonsense and borderline fraudulent commerce. It has to be said that if people spent one hundredth of the effort they put into considerations of diet into useful medical research, we'd be a lot closer to solving the problem of degenerative aging and age-related disease. So much light and noise for so little gain. No alteration you can make to your eating habits will reliabl Continue reading >>

Ketogenesis

Ketogenesis

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 >>

Ketogenesis

Ketogenesis

Also found in: Dictionary, Encyclopedia, Wikipedia. Related to ketogenesis: ketogenic diet ketogenesis [ke″to-jen´ĕ-sis] the production of ketone bodies. adj., adj ketogen´ic, ketogenet´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. ke·to·gen·e·sis (kē'tō-jen'ĕ-sis), Metabolic production of ketones or ketone bodies. ketogenesis /ke·to·gen·e·sis/ (-jen´ĕ-sis) the production of ketone bodies.ketogenet´icketogen´ic ketogenesis the formation or production of ketone bodies. ke·to·gen·e·sis (kē'tō-jen'ĕ-sis) Metabolic production of ketones or ketone bodies. ketogenesis The formation of acid KETONE BODIES, as in uncontrolled DIABETES, starvation or as a result of a diet with a very high fat content. ketogenesis the production of ketone bodies which occurs particularly during starvation. Continue reading >>

6 Health Benefits Of Ketogenesis And Ketone Bodies

6 Health Benefits Of Ketogenesis And Ketone Bodies

With heavy coverage in the media, ketogenic diets are all the rage right now. And for a good reason; for some people, they truly work. But what do all these different terms like ketogenesis and ketone bodies actually mean? Firstly, this article takes a look at what the ketogenesis pathway is and what ketone bodies do. Following this, it will examine six potential health benefits of ketones and nutritional ketosis. What is Ketogenesis? Ketogenesis is a biochemical process through which the body breaks down fatty acids into ketone bodies (we’ll come to those in a minute). Synthesis of ketone bodies through ketogenesis kicks in during times of carbohydrate restriction or periods of fasting. When carbohydrate is in short supply, ketones become the default energy source for our body. As a result, a diet to induce ketogenesis should ideally restrict carb intake to a maximum of around 50 grams per day (1, 2). Ketogenesis may also occur at slightly higher levels of carbohydrate intake, but for the full benefits, it is better to aim lower. When ketogenesis takes place, the body produces ketone bodies as an alternative fuel to glucose. This physiological state is known as ‘nutritional ketosis’ – the primary objective of ketogenic diets. There are various methods you can use to test if you are “in ketosis”. Key Point: Ketogenesis is a biological pathway that breaks fats down into a form of energy called ketone bodies. What Are Ketone Bodies? Ketone bodies are water-soluble compounds that act as a form of energy in the body. There are three major types of ketone body; Acetoacetate Beta-hydroxybutyrate Acetone (a compound created through the breakdown of acetoacetate) The first thing to remember is that these ketones satisfy our body’s energy requirements in the same w Continue reading >>

Ketogenesis And Ketone Utilization In Various Health Conditions

Ketogenesis And Ketone Utilization In Various Health Conditions

Part 1: Ketogenesis Ketones will only be created in the body if blood sugar and insulin concentration in the blood is low. If the body is in the process of ketogenesis (making ketones for fuel) and sugars/carbs are introduced, insulin will be released and ketogenesis will stop. Sugar and carbs are always the primary fuel. When glucose is not available, stored fat in adipose tissue is mobilized. This would occur during fasting. Fat is stored as a triglyceride, it its broken down by the enzyme “hormone sensitive lipase’ into 1 glycerol molecule and 3 fatty acid molecules. The fatty acids are then transported into the cell’s mitochondria with the aid of acetyl-L-carnitine where the process of turning fatty acid molecules into energy molecules (ATP) occurs. In the mitochondria, the process of beta-oxidation breaks the fatty acids down into smaller carbon chains (used for energy) and Acetyl CoA. In the process the Acetyl CoA accumulates, which triggers the process of ketogenesis. Within a few steps acetyl CoA is converted to acetoacetate which can then be converted into beta hydroxybutarate and acetone. These later 3 molecules are collectively known as ‘ketone bodies’. Without delay the ketones are used as a cellular fuel source in all tissues except for the liver. Primarily, the brain, heart and muscle tissue will use ketones efficiently when they are available. The main concept here is that stored fat breaks down into energy while simultaneously evoking the production of ketones, which, in turn, are used for energy. Part 2: Ketone utilization With a very low carb diet, prolonged fasting, and/or when taking supplemental/exogenous ketones, the concentration of ketones in the blood remains elevated and being in a ‘state of ketosis’ is based on the blood concentr Continue reading >>

The Biochemistry Of Ketogenesis And Its Role In Weight Management, Neurological Disease And Oxidative Stress

The Biochemistry Of Ketogenesis And Its Role In Weight Management, Neurological Disease And Oxidative Stress

Abstract Ketogenesis is the branch of mammalian metabolism concerned with the synthesis of ketone bodies. In this process, the small, water-soluble compounds acetoacetate, D-3-β-hydroxybutyrate and propanone are produced by the liver in response to reduced glucose availability. Although ketone bodies are always present at a low level in healthy individuals, dietary manipulation and certain pathological conditions can increase the levels of these compounds in vivo. In some instances, such as in refractory epilepsy, high levels of ketone bodies can be beneficial—in this instance, by exerting an anticonvulsant effect. Conversely, if the levels of ketones rise to supraphysiological levels, as can occur in diabetes mellitus, a state of ketoacidosis can occur, which has serious consequences for cellular function. More recently, research has identified a possible link between ketogenesis and free radical-mediated pathologies, highlighting the potential application of ketogenic diets to the treatment of conditions such as Alzheimer's disease. Overall, an understanding of ketone body metabolism and its links to human disease may prove to be vital in developing new regimens for the treatment of human disease. Notes This work was partially supported by the Northern Ireland R&D Office (Extension to RRG 5.42). The authors would like to thank Dr DJ Timson, School of Biological Sciences, Queen's University Belfast, for useful discussions of mammalian metabolism. Continue reading >>

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