diabetestalk.net

Ketogenesis

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 >>

Fatty Acid Oxidation And Ketogenesis

Fatty Acid Oxidation And Ketogenesis

transport in the blood a) adipose tissue: fat catabolism (lipolysis) -fat --> glycerol + 3 FFA -hormone sensitive lipase: breakdown fat in our internal stores -fasting (glucagon) and physical activity (epinephrine) b) FFA (unesterified or nonesterified) bind to albumin in the blood while glycerol is free and it circulates in the blood until it gets to the cells that need energy, enters the cell cytosol and stays there while FA doesnt because FA needs to move to mitochondria to be used as an energy source. glycerol is water soluble (composed of 3 carbon and 3 alcohol groups) c) in the cell, FFA binds to fatty acid-binding protein fatty acid oxidation we need to convert FA to acetyl CoA so we can use them in citric acid cylce as energy source FA--> acetyl CoA to do this reaction, mitochondria, and NAD(niacin), FAD (riboflavin) are needed as coenzymes formation of acetyl CoA is going to occur under below conditions, what happens to Acetyl CoA is different in all these situations: low carb diet, fasting, starvation, type I diabetes, exercise) beta-oxidation step 3 of activation of FFA acylcarnitine transported thru inner membrane by a protein -carnitine acylcarnitine translocase carnitine is used first because for every acylcarnitine that goes through inside the mitochondria, a molecule of free carnitine has to be transported outside the membrane simultaneouly to do the previous reaction for the next fatty acid, recyling carnitine we are transferring acylcarnitine through the membrane space to inner membrane (inside the matrix of mitochondria) beta oxidation formation of acetyl CoA from carboyxl end of FA, repeating until FA is completely oxidized fatty acid oxidases: enzymes involved in the oxidation process once the fatty acid is inside the mitochondria (acyl CoA), we can 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 >>

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 >>

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 >>

During This Time, The Biocyc Websites

During This Time, The Biocyc Websites

SRI International will be closed from close of business 22 Dec 2017 until opening of business 2 Jan 2018. Support issues logged while SRI is closed will be addressed when we re-open. (EcoCyc, HumanCyc, MetaCyc, BsubCyc) will be down for maintenance until noon Sunday, 31 Dec 2017 All times Pacific Standard Time Continue reading >>

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 >>

Creb3l3 Controls Fatty Acid Oxidation And Ketogenesis In Synergy With Pparα

Creb3l3 Controls Fatty Acid Oxidation And Ketogenesis In Synergy With Pparα

CREB3L3 is involved in fatty acid oxidation and ketogenesis in a mutual manner with PPARα. To evaluate relative contribution, a combination of knockout and transgenic mice was investigated. On a ketogenic-diet (KD) that highlights capability of hepatic ketogenesis, Creb3l3−/− mice exhibited reduction of expression of genes for fatty oxidation and ketogenesis comparable to Ppara−/− mice. Most of the genes were further suppressed in double knockout mice indicating independent contribution of hepatic CREB3L3. During fasting, dependency of ketogenesis on CREB3L3 is lesser extents than Ppara−/− mice suggesting importance of adipose PPARα for supply of FFA and hyperlipidemia in Creb3l3−/− mice. In conclusion CREB3L3 plays a crucial role in hepatic adaptation to energy starvation via two pathways: direct related gene regulation and an auto-loop activation of PPARα. Furthermore, as KD-fed Creb3l3−/− mice exhibited severe fatty liver, activating inflammation, CREB3L3 could be a therapeutic target for NAFLD. The common characteristics of metabolic disorders, such as obesity, diabetes, cardiovascular diseases, and fatty liver, impair nutrient homeostasis, which is tightly regulated by balancing energy production (e.g. ketogenesis, gluconeogenesis, and lipid synthesis) with energy utilization (e.g. lipid oxidation). As fasting progresses, metabolic substrates stored in white adipose tissue (WAT) are released into the circulation as glycerol and free fatty acids (FFA) and transported into the liver. The liver then adapts by increasing β-oxidation, which converts fatty acids into acetyl coenzyme A (acetyl-coA), and by increasing ketogenesis, which converts the resulting acetyl-CoA into ketone bodies. The first ketone body formed from acetyl-CoA is acetoacetate Continue reading >>

Study Of The Mechanism Of Inhibition Of Ketogenesis By Propionate In Bovine Liver

Study Of The Mechanism Of Inhibition Of Ketogenesis By Propionate In Bovine Liver

R. S. BUSH and , L. P. MILLIGAN Propionate caused an inhibition of ketogenesis from butyrate by bovine liver slices. When succinate, fumarate and aspartate were included in the incubation mixtures as sources of oxaloacetate, they were not as inhibitory as propionate. The possibility of competition between propionate and butyrate for cofactors required for activation was discounted when neither ATP (17 mM), nor carnitine (3.5 mM), added to expand the coenzyme A (CoA) pool, relieved the antiketogenic effect of propionate. The 3-hydroxy-3-methylglutaryl-CoA pathway appeared to be the major route for formation of acetoacetate from acetoacetyl-CoA in liver extracts, on the basis of enzyme assays. At a concentration of 0.5 mM, propionyl-CoA caused an apparent decrease of 3-hydroxy-3-methylglutaryl-CoA synthase activity of 46%, whereas propionate and methylmalonyl-CoA were not effective. At a concentration of 15 mM, propionate resulted in 30% inhibition of synthase activity. Propionyl-CoA did not affect the activity of 3-hydroxy-3-methylglutaryl-CoA lyase. It was suggested that in bovine liver the antiketogenic effect of propionate is achieved, at least in part, through inhibition of formation of acetoacetate from acetoacetyl-CoA. Abstract The activities of various enzymes involved in formation of acetoacetate from acetoacetyl-coenzyme A (acetoacetyl-CoA) were investigated using crude extracts of rumen papillae. Acetoacetyl-CoA deacylase and 3-hydroxy-3-methylglutaryl-CoA synthase were measurable in these extracts, but addition of succinate (15 mM) produced an increased activity of acetoacetyl-CoA removal which was up to threefold, or more, that of deacylase. Succinyl-CoA was identified as a product of the reaction in the presence of succinate, indicating that 3-oxo acid CoA t Continue reading >>

Ketogenesis (biosynthesis Of Ketone Bodies)

Ketogenesis (biosynthesis Of Ketone Bodies)

In humans, liver mitochondria have capacity to divert any excess acetyl-CoA formed in the liver during oxidation of fatty acids or oxidation of pyruvate that exceed capacity of citric acid cycle to undergo conversion to the ketone bodies. ketone bodies : [acetoacetate, D-β-hydroxybutyrate& acetone (non metabolizable side product)] for export to other tissues, where they can reconvert to acetyl CoA & oxidized by citric acid cycle. * Ketone bodies are important sources of energy for the peripheral tissues because: They are soluble in aqueous solution (don't need to be incorporated into lipoproteins or carried by albumin like lipid). 2. Produced in liver during periods when acetyl-CoA present exceed the oxidative capacity of the liver. How 3. They are used in proportion to their concentration in the blood by extrahepatic tissues (skeletal & cardiac muscle & renal cortex). Brain, heart & muscle can use ketone bodies to meet their energy needs if the blood levels rise sufficiently (during prolonged periods of fasting). Why ketone bodies synthesized by the liver: The production and export of ketone bodies from the liver to extrahepatic tissues allow continued oxidation of fatty acids in the liver when acetyl-CoA is not being oxidized in the citric acid cycle. * Synthesis of ketone bodies 1-Formation of acetoacetyl CoA can occur by one of 2 processes: a. Incomplete breakdown of fatty acid. b. Enzymatic condensation of two molecules of acetyl-CoA, which catalyzed by thiolase (the reversal of thiolase reaction of fatty acid oxidation). 2- The acetoacetyl-CoA, condenses with 3rd molecule of acetyl-CoA to form β -hydroxy- β -methylglutaryl-CoA (HMG-CoA) catalyzed by HMG-CoA synthase (the rate limiting step in the synthesis of ketone bodies & present in significant quantit 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 >>

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

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 >>

Disorders Of Ketogenesis And Ketolysis

Disorders Of Ketogenesis And Ketolysis

Disorders of ketone body metabolism are characterized by episodes of metabolic decompensation. The initial episode usually occurs in the newborn period or early childhood during an infection with vomiting. The disorders of ketogenesis cause hypoglycemia and encephalopathy. Decompensation leads to severe ketoacidosis in defects of ketone body utilization (including MCT1 transporter deficiency). Treatment aims to prevent the catabolism that leads to decompensation. Prolonged fasting is avoided and glucose is provided, orally or intravenously, during illnesses. The risk of decompensation falls with age, particularly for disorders of ketolysis. There have, however, been some fatal episodes in adults with HMG-CoA lyase deficiency, including during pregnancy. Access to the complete content on Oxford Medicine Online requires a subscription or purchase. Public users are able to search the site and view the abstracts for each book and chapter without a subscription. Please subscribe or login to access full text content. If you have purchased a print title that contains an access token, please see the token for information about how to register your code. For questions on access or troubleshooting, please check our FAQs, and if you can't find the answer there, please contact us. Glut1 Deficiency (Glut1D, OMIM #606777) is caused by impaired glucose transport into the brain. The resulting cerebral “energy crisis” causes intractable seizures, developmental delay, and a complex movement disorder. The diagnosis is based on clinical features, low CSF glucose and/or mutations in the SLC2A1 gene. Paroxysmal exertion-induced dystonia (PED) and hereditary cryohydrocytosis have been described as allelic variants. Adults are increasingly being recognized through family pedigrees. The con Continue reading >>

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 >>

More in ketosis