Preferential Utilization Of Ketone Bodies For The Synthesis Of Myelin Cholesterol In Vivo.
Abstract 1. The distribution of radioactivity among lipid classes of myelin and other subcellular brain fractions of young rats (18-21 days) was determined after in vivo injection of (3-(14)C-labelled ketone bodies, [U-(14)C] glucose or [2-(14)C] glucose. 2. The incorporation ratios (sterol/fatty acids) were 0.67, 1.48, 0.25, 0.62 and 0.54 for whole brain, myelin, mitochondria, microsomes and synaptosomes, respectively, with (3-(14)C)-labelled ketone bodies as substrate and 0.37, 0.89, 0.19, 0.34 and 0.29 with [U-(14)C] glucose as substrate. These data show that, both in whole brain and in subcellular brain fractions, acetyl groups derived from ketone bodies are used for sterol synthesis to a large extent than acetyl groups originating from glucose. 3. The specific radioactivity of cholesterol is much higher in myelin than in whole brain or in the other brain fractions, particularly after administration of labelled ketone bodies as substrate. 4. The incorporation patterns of acetoacetate and D-3-hydroxybutyrate were very similar, indicating that both ketone bodies contribute acetyl groups for lipid synthesis via the same metabolic route. 5. Our data suggest that a direct metabolic path from ketone bodies towards cholesterol exists - possibly via acetoacetyl-CoA formation in the cytosol of brain cells - and that this process is most active in oligodendrocytes. Continue reading >>
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 >>
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 >>
Triacylglycerols - Major Form Of Energy Storage In Animals
Lipid Metabolism Remember fats?? Your energy reserves: ~0.5% carbs (glycogen + glucose) ~15% protein (muscle, last resort) ~85% fat Why use fat for energy? 1 gram fat = at least 6-fold more energy than 1 gram carb Sources of fat: 1. Diet 2. Stored fat (adipose tissue) 3. Fat synthesized in one organ for export to another (excess carb converted to fat) Lipid Metabolism Hormones trigger mobilization of stored triacylglycerols Also heart, renal cortex Epinephrine, glucagon Lipid Metabolism How are fatty acids burned for energy? 1. Transported to mitochondria 2. Oxidized to produce acetyl CoA, NADH, FADH2 3. Acetyl CoA goes to citric acid cycle NADH, FADH2 donate e- to oxidative phos Lipid Metabolism Oxidation of fatty acids - fatty acid breakdown Transport of fatty acids into mitochondria â€œPrimeâ€ fatty acid Drives reaction Lipid Metabolism Oxidation of fatty acids - fatty acid breakdown Transport into mitochondria using carnitine intermediate Carnitine recycled Cytosolic and mitochondrial CoA pools stay balanced (CoAmatrix used for ox degrad of pyruvate, fatty acids, amino acids) (CoAcytosol used for fatty acid biosynthesis) Lipid Metabolism Oxidation of fatty acids - fatty acid breakdown b-oxidation of fatty acids (even # carbons) oxidized reduced Donates 2e- to Q (ox phos) oxidation hydration oxidation thiolysis Citric acid cycle Fatty acid shortened by 2 carbon atoms, cycle through b-oxidation again Oxidation of fatty acids - fatty acid breakdown b-oxidation of fatty acids (odd # carbons) b-oxidation gives a 3 carbon remnant Need ATP to put CO2 on biotin (Citric acid cycle intermediate) Lipid Metabolism Oxidation of fatty acids - regulation Need to regulate so oxidation only occurs when the need for energy requires it 1. Rate-limiting rxn. - fatty acids enteri Continue reading >>
Biochemistry 10: Lipid Metabolism
These are notes from lecture 10 of Harvard Extension’s biochemistry class. intake and distribution of fats Fat can be consumed directly in the diet or derived (by the liver) from excess dietary carbohydrates. Once stored, it can be re-mobilized from adipose tissue. Typical humans (in developed countries??) get ~40% of their calories from dietary fat. Triacylglycerols (TAGs) are broken down by lipases. Pancreatic lipases in the intestinal lumen help to absorb fatty acids from the diet into the intestine. Lipoprotein lipases in the capillary walls help absorb fatty acid from chylomicrons and VLDLs into target tissues. Hormone-sensitive lipases inside cells break down fat stores in adipose tissue. Bile salts are various derivatives of cholesterol with different R2 groups at the end of the chain. The bile salt acts as a detergent, breaking apart large dietary globules of fat to yield smaller micelles, which are more accessible to lipases than the large globules. Intestinal lipases then convert TAGs into mono- and di-acylglycerols, free fatty acids, and glycerol. Now the TAGs need to somehow travel through the blood to be of use as energy to other organs. This is accomplished by packaging them into lipoproteins. A lipoprotein is a ball with a single-layered phospholipid + cholesterol surface, filled with triacylglycerols and cholesterol esters (cholesterol with a fatty acid attached). Apolipoproteins are embedded in the surface. class abbreviation density protein lipid content chylomicrons CM lowest lowest highest very low density lipoproteins VLDL .. .. .. intermediate density lipoproteins* IDL .. .. .. low density lipoproteins LDL .. .. .. high density lipoproteins HDL highest highest lowest *Yes, this is not a mistake; IDL is really in between VLDL and LDL, not between Continue reading >>
What Are The Advantages Of Eating A High-fat Diet For Weight Loss, Rather Than Simply Fasting?
You can actually do both and lose weight very effectively, in addition to gaining many other health benefits. As someone else mentioned, the ketogenic diet actually is not a fad diet but has research to prove its effectiveness, and I personally have seen its benefits. Many also incorporate intermittent fasting with keto, but it’s not a requirement. I do recommend watching some of Dr. Jason Fung’s videos on fasting for really interesting information on how fasting intermittently can be very healthy in a lot of ways. So if you’re not familiar, the keto diet has the optimum ratios of macronutrients: fat, protein, and carbohydrates. There has been a great deal of debate in recent years on what those ratios should be, and it does vary from person to person. However, research is showing that what we were led to believe in the past, that eating fat makes you fat, is dead wrong. Eating a diet high in fat, moderate in protein, and very low in carbohydrates, such as the ketogenic diet (or commonly known as “keto”), puts your body into a state of ketosis, a natural metabolic state in which your body is no longer using glucose as its main source of fuel, and instead it begins using ketones to get its energy. Ketones are produced when your body is burning fat because no glucose is available. It is important not to confuse ketosis, a completely harmless and normal metabolic state, with ketoacidosis, a dangerous condition that occurs mostly in type 1 diabetics when they create high levels of both glucose and ketones at the same time. On the ketogenic plan, blood glucose usually drops, so this is not a danger for most people. However, if you are a type 1 diabetic, check with your doctor before switching to the ketogenic way of eating. So being in ketosis simply means that you Continue reading >>
What Is Ketosis Diet And What Does It Contain?
A keto diet is well known for being a low carb diet, where the body produces ketones in the liver to be used as energy. It’s referred to as many different names – ketogenic diet, low carb diet, low carb high fat (LCHF), etc. When you eat something high in carbs, your body will produce glucose and insulin. Glucose is the easiest molecule for your body to convert and use as energy, so it will be chosen over any other energy source. Insulin is produced to process the glucose in your bloodsteam, by taking it around the body. Since the glucose is being used as a primary energy, your fats are not needed, and are therefore stored. Typically on a normal, higher carbohydrate diet, the body will use glucose as the main form of energy. By lowering the intake of carbs, the body is induced into a state known as ketosis. Ketosis is a natural process the body initiates to help us survive when food intake is low. During this state, we produce ketones, which are produced from the breakdown of fats in the liver. The end goal of a properly maintained keto diet is to force your body into this metabolic state. We don’t do this through starvation of calories, but through starvation of carbohydrates. Our bodies are extremely adaptive to what you put into it – when you overload it with fats and take away carbohydrates, it will begin to burn ketones as the main energy source. Cholesterol. A keto diet has shown to improve triglyceride levels and cholesterol levels most associated with arterial buildup. Weight Loss. As your body is burning fat as the main source of energy, you will essentially be using your fat stores as an energy source while in a fasting state. Blood Sugar. Many studies show the decrease of LDL cholesterol over time and have shown to eliminate ailments such as type 2 di Continue reading >>
Acetyl Coa - Cross Roads Compound
Metabolic Fates of Acetyl CoA: If you reflect on both the content lipid metabolism and the previous carbohydrate metabolism, you can appreciate that there is a special central role for acetyl CoA. Acetyl CoA acts both as a metabolic "receiving and shipping department" for all classes of biomolecules and as a major source of useful metabolic energy. The diagram on the left summarizes all metabolism and the central role of acetyl CoA. The diagram the next lower panel focuses on other functions as well. The interactions of amino acids with acetyl CoA and the citric acid cycle will be studied in protein metabolism. Notice that acetyl CoA can react "reversibly" in the degradation or synthesis of lipids and amino acids. This is not the case with carbohydrate metabolism. In mammals, it is impossible to use acetyl CoA to make carbohydrates. Synthesis of Cholesterol and other Steroids: Without going into detail, acetyl CoA forms the basis from which the fairly complicated steroids are synthesized. Some steroids of importance include cholesterol, bile salts, sex hormones, aldosterone, and cortisol. The major concern about cholesterol in the diet is muted somewhat by the knowledge that the liver can and does synthesize all of the cholesterol that the body needs. Excess cholesterol, whether from food or synthesized by the liver, ends up in the blood stream where it builds up on the artery walls. It has been determined that cholesterol levels can be controlled by lowering the amount of saturated fat and increasing the unsaturated fats. Unsaturated fats seem to speed the rate at which cholesterol breaks down in the blood. Controlling fats and cholesterol in the diet can significantly affect the levels of these substances in the blood. Lipogenesis: Since carbohydrates are the major pa Continue reading >>
on on Fats (or triglycerides) within the body are ingested as food or synthesized by adipocytes or hepatocytes from carbohydrate precursors ([link]). Lipid metabolism entails the oxidation of fatty acids to either generate energy or synthesize new lipids from smaller constituent molecules. Lipid metabolism is associated with carbohydrate metabolism, as products of glucose (such as acetyl CoA) can be converted into lipids. Lipid metabolism begins in the intestine where ingested triglycerides are broken down into smaller chain fatty acids and subsequently into monoglyceride molecules (see [link]b) by pancreatic lipases, enzymes that break down fats after they are emulsified by bile salts. When food reaches the small intestine in the form of chyme, a digestive hormone called cholecystokinin (CCK) is released by intestinal cells in the intestinal mucosa. CCK stimulates the release of pancreatic lipase from the pancreas and stimulates the contraction of the gallbladder to release stored bile salts into the intestine. CCK also travels to the brain, where it can act as a hunger suppressant. Together, the pancreatic lipases and bile salts break down triglycerides into free fatty acids. These fatty acids can be transported across the intestinal membrane. However, once they cross the membrane, they are recombined to again form triglyceride molecules. Within the intestinal cells, these triglycerides are packaged along with cholesterol molecules in phospholipid vesicles called chylomicrons ([link]). The chylomicrons enable fats and cholesterol to move within the aqueous environment of your lymphatic and circulatory systems. Chylomicrons leave the enterocytes by exocytosis and enter the lymphatic system via lacteals in the villi of the intestine. From the lymphatic system, the chylo Continue reading >>
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 >>
Replacing The Cholesterol Hydroxyl Group With The Ketone Group Facilitates Sterol Flip-flop And Promotes Membrane Fluidity
Abstract The 3α-hydroxyl group is a characteristic structural element of all membrane sterol molecules, while the 3-ketone group is more typically found in steroid hormones. In this work, we investigate the effect of substituting the hydroxyl group in cholesterol with the ketone group to produce ketosterone. Extensive atomistic molecular dynamics simulations of saturated lipid membranes with either cholesterol or ketosterone show that, like cholesterol, ketosterone increases membrane order and induces condensation. However, the effect of ketosterone on membrane properties is considerably weaker than that of cholesterol. This is largely due to the unstable positioning of ketosterone at the membrane−water interface, which gives rise to a small but significant number of flip-flop transitions, where ketosterone is exchanged between membrane leaflets. This is remarkable, as flip-flop motions of sterol molecules have not been previously reported in analogous lipid bilayer simulations. In the same context, ketosterone is found to be more tilted with respect to the membrane normal than cholesterol. The atomic level mechanism responsible for the increase of the steroid tilt and the promotion of flip-flops is the decrease in polar interactions at the membrane−water interface. Interactions between lipids or water and the ketone group are found to be weaker than in the case of the hydroxyl group, which allows ketosterone to penetrate through the hydrocarbon region of a membrane. Department of Physical Chemistry, Barcelona University, c/ Marti i Franques 1, Pta 4, 08028 Barcelona, Spain, Department of Physics, Tampere University of Technology, Tampere, Finland, Department of Applied Mathematics, The University of Western Ontario, London (ON), Canada, Department of Applied Physi Continue reading >>
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 >>
Effects Of Exogenous Ketone Supplementation On Blood Ketone, Glucose, Triglyceride, And Lipoprotein Levels In Sprague–dawley Rats
Abstract Nutritional ketosis induced by the ketogenic diet (KD) has therapeutic applications for many disease states. We hypothesized that oral administration of exogenous ketone supplements could produce sustained nutritional ketosis (>0.5 mM) without carbohydrate restriction. We tested the effects of 28-day administration of five ketone supplements on blood glucose, ketones, and lipids in male Sprague–Dawley rats. The supplements included: 1,3-butanediol (BD), a sodium/potassium β-hydroxybutyrate (βHB) mineral salt (BMS), medium chain triglyceride oil (MCT), BMS + MCT 1:1 mixture, and 1,3 butanediol acetoacetate diester (KE). Rats received a daily 5–10 g/kg dose of their respective ketone supplement via intragastric gavage during treatment. Weekly whole blood samples were taken for analysis of glucose and βHB at baseline and, 0.5, 1, 4, 8, and 12 h post-gavage, or until βHB returned to baseline. At 28 days, triglycerides, total cholesterol and high-density lipoprotein (HDL) were measured. Exogenous ketone supplementation caused a rapid and sustained elevation of βHB, reduction of glucose, and little change to lipid biomarkers compared to control animals. This study demonstrates the efficacy and tolerability of oral exogenous ketone supplementation in inducing nutritional ketosis independent of dietary restriction. Background Emerging evidence supports the therapeutic potential of the ketogenic diet (KD) for a variety of disease states, leading investigators to research methods of harnessing the benefits of nutritional ketosis without the dietary restrictions. The KD has been used as an effective non-pharmacological therapy for pediatric intractable seizures since the 1920s [1–3]. In addition to epilepsy, the ketogenic diet has elicited significant therapeut Continue reading >>
Introduction To Degradation Of Lipids And Ketone Bodies Metabolism
Content: 1. Introduction to degradation of lipids and ketone bodies metabolism 2. Lipids as source of energy – degradation of TAG in cells, β-oxidation of fatty acids 3. Synthesis and utilisation of ketone bodies _ Triacylglycerol (TAG) contain huge amounts of chemical energy. It is very profitable to store energy in TAG because 1 g of water-free TAG stores 5 times more energy than 1 g of hydrated glycogen. Complete oxidation of 1 g of TAG yields 38 kJ, 1g of saccharides or proteins only 17 kJ. Man that weighs 70 kg has 400 000 kJ in his TAG (that weight approximately 10,5 kg). This reserve of energy makes us able to survive starving in weeks. TAG accumulate predominantly in adipocyte cytoplasm. There are more types of fatty acid oxidation. Individual types can be distinguished by different Greek letters. Greek letter denote atom in the fatty acid chain where reactions take place. β-oxidation is of major importance, it is localised in mitochondrial matrix. ω- and α- oxidation are localised in endoplasmic reticulum. Animal cells cannot convert fatty acids to glucose. Gluconeogenesis requires besides other things (1) energy, (2) carbon residues. Fatty acids are rich source of energy but they are not source of carbon residues (there is however one important exception, i.e. odd-numbered fatty acids). This is because cells are not able to convert AcCoA to neither pyruvate, nor OAA. Both carbons are split away as CO2. PDH is irreversible. Plant cells are capable of conversion of AcCoA to OAA in glyoxylate cycle. _ Lipids as source of energy – degradation of TAG in cells, β-oxidation of fatty acids Lipids are used for energy production, this process take place in 3 phases: 1) Lipid mobilisation – hydrolysis of TAG to FA and glycerol. FA and glycerol are transported Continue reading >>
The term “ketone bodies” refers primarily to two compounds: acetoacetate and β‐hydroxy‐butyrate, which are formed from acetyl‐CoA when the supply of TCA‐cycle intermediates is low, such as in periods of prolonged fasting. They can substitute for glucose in skeletal muscle, and, to some extent, in the brain. The first step in ketone body formation is the condensation of two molecules of acetyl‐CoA in a reverse of the thiolase reaction. The product, acetoacetyl‐CoA, accepts another acetyl group from acetyl‐CoA to form β‐hydroxy‐β‐hydroxymethylglutaryl‐CoA (HMG‐CoA). HMG‐CoA has several purposes: It serves as the initial compound for cholesterol synthesis or it can be cleaved to acetoacetate and acetyl‐CoA. Acetoacetate can be reduced to β‐hydroxybutyrate or can be exported directly to the bloodstream. Acetoacetate and β‐hydroxybutyrate circulate in the blood to provide energy to the tissues. Acetoacetate can also spontaneously decarboxylate to form acetone: Although acetone is a very minor product of normal metabolism, diabetics whose disease is not well‐managed often have high levels of ketone bodies in their circulation. The acetone that is formed from decarboxylation of acetoacetate is excreted through the lungs, causing characteristic “acetone breath.” Continue reading >>