Ketone Body Metabolism
Ketone body metabolism includes ketone body synthesis (ketogenesis) and breakdown (ketolysis). When the body goes from the fed to the fasted state the liver switches from an organ of carbohydrate utilization and fatty acid synthesis to one of fatty acid oxidation and ketone body production. This metabolic switch is amplified in uncontrolled diabetes. In these states the fat-derived energy (ketone bodies) generated in the liver enter the blood stream and are used by other organs, such as the brain, heart, kidney cortex and skeletal muscle. Ketone bodies are particularly important for the brain which has no other substantial non-glucose-derived energy source. The two main ketone bodies are acetoacetate (AcAc) and 3-hydroxybutyrate (3HB) also referred to as β-hydroxybutyrate, with acetone the third, and least abundant. Ketone bodies are always present in the blood and their levels increase during fasting and prolonged exercise. After an over-night fast, ketone bodies supply 2–6% of the body's energy requirements, while they supply 30–40% of the energy needs after a 3-day fast. When they build up in the blood they spill over into the urine. The presence of elevated ketone bodies in the blood is termed ketosis and the presence of ketone bodies in the urine is called ketonuria. The body can also rid itself of acetone through the lungs which gives the breath a fruity odour. Diabetes is the most common pathological cause of elevated blood ketones. In diabetic ketoacidosis, high levels of ketone bodies are produced in response to low insulin levels and high levels of counter-regulatory hormones. Ketone bodies The term ‘ketone bodies’ refers to three molecules, acetoacetate (AcAc), 3-hydroxybutyrate (3HB) and acetone (Figure 1). 3HB is formed from the reduction of AcAc i Continue reading >>
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. 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. 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. Other cells are capable of carrying out ketogenesis, but they are not as effective at doing so. Ketogenesis occurs constantly in a healthy individual. 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 type 1 (but not 2) diabetes), particularly during periods of "ketogenic stress" such as intercurrent illness. 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 >>
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 >>
Overview Structure two types acetoacetate β-hydroxybutyrate β-hydroxybutyrate + NAD+ → acetoacetate + NADH ↑ NADH:NAD+ ratio results in ↑ β-hydroxybutyrate:acetoacetate ratio 1 ketone body = 2 acetyl-CoA Function produced by the liver brain can use ketones if glucose supplies fall >1 week of fasting can provide energy to body in prolonged energy needs prolonged starvation glycogen and gluconeogenic substrates are exhausted can provide energy if citric acid cycle unable to function diabetic ketoacidosis cycle component (oxaloacetate) consumed for gluconeogenesis alcoholism ethanol dehydrogenase consumes NAD+ (converts to NADH) ↑ NADH:NAD+ ratio in liver favors use of oxaloacetate for ketogenesis rather than gluconeogenesis. RBCs cannot use ketones as they lack mitochondria Synthesis occurs in hepatocyte mitochondria liver cannot use ketones as energy lacks β-ketoacyl-CoA transferase (thiophorase) which converts acetoacetate to acetoacetyl under normal conditions acetoacetate = β-hydroxybutyrate HMG CoA synthase is rate limiting enzyme Clinical relevance ketoacidosis pathogenesis ↑ ketone levels caused by poorly controlled type I diabetes mellitus liver ketone production exceeds ketone consumption in periphery possible in type II diabetes mellitus but rare alcoholism chronic hypoglycemia results in ↑ ketone production presentation β-hydroxybutyrate > acetoacetate due to ↑ NADH:NAD+ ratio acetone gives breath a fruity odor polyuria ↑ thirst tests ↓ plasma HCO3 hypokalemia individuals are initially hyperkalemic (lack of insulin + acidosis) because K leaves the cells overall though the total body K is depleted replete K in these patients once the hyperkalemia begins to correct nitroprusside urine test for ketones may not be strongly + does not detect Continue reading >>
The Ketogenic Diet And Cholesterol
A common misconception is that because ketogenic diets are high in fat, they must increase cholesterol in your body and clog your arteries. However, much of the recent research shines light on how low-carb diets can optimize your cholesterol levels and in fact improve your heart health. Here we show the most up-to-date research on how different types of cholesterol impact the body and how the ketogenic diet can be a useful tool in maintaining a robust cardiovascular system. Cutting through the Fat: What are Lipids and Cholesterol? Before we can examine the research, we need to understand the roles fat, cholesterol, and carrier molecules called lipoproteins play in the body. Fats, also known as lipids, are a diverse group of molecules with a “non-polar” characteristic that repels water. This means that you if you put a fat such as oil or grease in water they will not mix. In the human body, fats are most commonly found in the bloodstream in one of two forms. The first is triglycerides, a fatty acid that stores energy for later use. These long molecules can be broken down into other fatty acids and glycerol to create fuel for the body. Glycerol can further be broken down into forms of glucose. Elevated levels of triglycerides in your blood can increase your risk of developing diabetes, cardiovascular illnesses, and other life-threatening diseases.  The other important class of lipids in the body is a waxy substance called cholesterol. These molecules have a variety of functions in your body such as building hormones including estrogen and testosterone, maintaining the integrity of cell membranes, and aiding in the absorption of vitamins. Your body produces all the cholesterol you need through the liver and other body cells. Cholesterol is also obtained by consuming 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 >>
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 >>
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How Does A Ketogenic Diet Change Your Life?
The ketogenic diet has changed many people’s lives in different ways: from weight loss to reversing diabetes to improving multiple health factors. 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 have switched from being a sugar-burner to a fat-burner. Ketones are created when you are metabolizing fat, whether it is from the fat in the foods you eat or from the fat around your belly. The ketogenic diet also is an anti-inflammatory way of eating. Chronic inflammation has been shown to be a significant contributor to metabolic syndrome, which includes obesity, insulin resistance, high blood pressure, and high cholesterol levels. Keto avoids foods that can cause inflammation, notably grains, sugar, and starchy carbohydrates such as potatoes and rice. Reducing inflammation may also improve leptin function in the body. Leptin is a hormone that sends signals to the brain that you have enough energy stored and that you are satiat Continue reading >>
westonaprice.org medicines/ Dangers of Statin Drugs: What You Haven’t Been Told About Popular Cholesterol-Lowering Medicines Sally Fallon and Mary G. Enig, PhD Hypercholesterolemia is the health issue of the 21st century. It is actually an invented disease, a “problem” that emerged when health professionals learned how to measure cholesterol levels in the blood. High cholesterol exhibits no outward signs–unlike other conditions of the blood, such as diabetes or anemia, diseases that manifest telltale symptoms like thirst or weakness–hypercholesterolemia requires the services of a physician to detect its presence. Many people who feel perfectly healthy suffer from high cholesterol–in fact, feeling good is actually a symptom of high cholesterol! Doctors who treat this new disease must first convince their patients that they are sick and need to take one or more expensive drugs for the rest of their lives, drugs that require regular checkups and blood tests. But such doctors do no work in a vacuum–their efforts to convert healthy people into patients are bolstered by the full weight of the US government, the media and the medical establishment, agencies that have worked in concert to disseminate the cholesterol dogma and convince the population that high cholesterol is the forerunner of heart disease and possibly other diseases as well. Who suffers from hypercholesterolemia? Peruse the medical literature of 25 or 30 years ago and you’ll get the following answer: any middle-aged man whose cholesterol is over 240 with other risk factors, such as smoking or overweight. After the Cholesterol Consensus Conference in 1984, the parameters changed; anyone (male or female) with cholesterol over 200 could receive the dreaded diagnosis and a prescription for pills. Re Continue reading >>
Ketone bodies Acetone Acetoacetic acid (R)-beta-Hydroxybutyric acid Ketone bodies are three water-soluble molecules (acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone) that are produced by the liver from fatty acids during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, prolonged intense exercise,, alcoholism or in untreated (or inadequately treated) type 1 diabetes mellitus. These ketone bodies are readily picked up by the extra-hepatic tissues, and converted into acetyl-CoA which then enters the citric acid cycle and is oxidized in the mitochondria for energy. In the brain, ketone bodies are also used to make acetyl-CoA into long-chain fatty acids. Ketone bodies are produced by the liver under the circumstances listed above (i.e. fasting, starving, low carbohydrate diets, prolonged exercise and untreated type 1 diabetes mellitus) as a result of intense gluconeogenesis, which is the production of glucose from non-carbohydrate sources (not including fatty acids). They are therefore always released into the blood by the liver together with newly produced glucose, after the liver glycogen stores have been depleted (these glycogen stores are depleted after only 24 hours of fasting). When two acetyl-CoA molecules lose their -CoAs, (or Co-enzyme A groups) they can form a (covalent) dimer called acetoacetate. Beta-hydroxybutyrate is a reduced form of acetoacetate, in which the ketone group is converted into an alcohol (or hydroxyl) group (see illustration on the right). Both are 4-carbon molecules, that can readily be converted back into acetyl-CoA by most tissues of the body, with the notable exception of the liver. Acetone is the decarboxylated form of acetoacetate which cannot be converted Continue reading >>
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 >>
How Can I Lose Weight As A Diabetic Who Hates Veggies?
Many veggies are high in carbohydrates, so while many vegetables provide a lot of the micronutrients (vitamins & minerals) you need, you don’t need to eat a diet that is primarily full of veggies to lose weight. The best kind of balanced diet is one that 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 have switched from being a sugar-burner to a fat-burner. Ketones are created when you are metabolizing fat, whether it is from the fat in the foods you eat or from the fat around your belly. The ketogenic diet also is an anti-inflammatory way of eating. Chronic inflammation has been shown to be a significant 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 >>
On This Site Tests: Urine Ketones (see Urinalysis - The Chemical Exam); Blood Gases; Glucose Tests Elsewhere On The Web Ask a Laboratory Scientist Your questions will be answered by a laboratory scientist as part of a voluntary service provided by one of our partners, the American Society for Clinical Laboratory Science (ASCLS). Click on the Contact a Scientist button below to be re-directed to the ASCLS site to complete a request form. If your question relates to this web site and not to a specific lab test, please submit it via our Contact Us page instead. Thank you. 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 >>
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