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Ketones Are Produced From Cholesterol

Ketone Bodies As Signaling Metabolites

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 >>

How Does A Ketogenic Diet Change Your Life?

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 >>

The Ketogenic Diet And Cholesterol

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. [1] 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 >>

Preferential Utilization Of Ketone Bodies For The Synthesis Of Myelin Cholesterol In Vivo.

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 >>

Fenofibrate Induces Ketone Body Production In Melanoma And Glioblastoma Cells

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 >>

Ketone Bodies

Ketone Bodies

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[1] during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, prolonged intense exercise,[2], 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.[3] 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).[1] 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)[1]. 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 >>

How Can I Lose Weight As A Diabetic Who Hates Veggies?

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 >>

Ketone Bodies

Ketone Bodies

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 >>

Ketone Ester Effects On Metabolism And Transcription

Ketone Ester Effects On Metabolism And Transcription

Abstract Ketosis induced by starvation or feeding a ketogenic diet has widespread and often contradictory effects due to the simultaneous elevation of both ketone bodies and free fatty acids. The elevation of ketone bodies increases the energy of ATP hydrolysis by reducing the mitochondrial NAD couple and oxidizing the coenzyme Q couple, thus increasing the redox span between site I and site II. In contrast, metabolism of fatty acids leads to a reduction of both mitochondrial NAD and mitochondrial coenzyme Q causing a decrease in the ΔG of ATP hydrolysis. In contrast, feeding ketone body esters leads to pure ketosis, unaccompanied by elevation of free fatty acids, producing a physiological state not previously seen in nature. The effects of pure ketosis on transcription and upon certain neurodegenerative diseases make approach not only interesting, but of potential therapeutic value. PRODUCTION OF KETONE BODIES Ketone bodies are formed in the liver from free fatty acids released from adipose tissue. As the blood concentration of free fatty acids increases, concentration of blood ketone bodies is correspondingly increased (1, 2). Ketone bodies serve as a physiological respiratory substrate and are the physiological response to prolonged starvation in man (3, 4), where the blood level of ketones reaches 5–7 mM (5). If the release of free fatty acids from adipose tissue exceeds the capacity of tissue to metabolize them, as occurs during insulin deficiency of type I diabetes or less commonly in the insulin resistance of type II diabetes, severe and potentially fatal diabetic ketoacidosis can occur, where blood ketone body levels can reach 20 mM or higher (2) resulting in a decrease in blood bicarbonate to almost 0 mM and blood pH to 6.9. Diabetic ketoacidosis, which is a Continue reading >>

Introduction To Cholesterol Metabolism

Introduction To Cholesterol Metabolism

After the attachment of the decaprenyl group the aromatic ring undergoes a series of modifications. The first modification is a hydroxylation reaction at carbon 5 of the benzene ring. This hydroxylation is catalyzed by the FAD-dependent monooxygenase encoded by the COQ6 gene. The COQ6 gene is located on chromosome 14q24.3 and is composed of 15 exons that generate two alternatively spliced mRNAs each encoding a distinct protein isoform. In the next reaction the newly attached hydroxyl group undergoes an O-methylation reaction catalyzed by the mitochondrial SAM-dependent O-methyltransferase encoded by the COQ3 gene. The COQ3 gene is located on chromosome 6q16.2 and is composed of 9 exons that encode a 369 amino acid protein. The next reaction involves decarboxylation of the carboxylic acid group attached to carbon 1 of the benzene ring leaving a hydroxyl group. The decarboxylation reaction is catalyzed by an as yet uncharacterized enzyme. These three reactions result in the formation of 2-methoxy-6-decaprenylphenol. In the next reaction, carbon 2 of the benzene ring is methylated. The C-methylation reaction is catalyzed by the mitochondrial SAM-dependent enzyme identified as 2-methoxy-6-polyprenyl-1,4-benzoquinol methylase. This methylase is encoded by the COQ5 gene which is located on chromosome 12q24.31 and is composed of 8 exons that encode a 327 amino acid protein. The next reaction involves the hydroxylation of carbon 6 of the benzene ring. This hydroxylation is catalyzed by 5-demethoxyubiquinone hydroxylase which is encoded by the COQ7 gene. The COQ7 gene is located on chromosome 16p12.3 and is composed of 8 exons that generate two alternatively spliced mRNAs both of which encode distinct protein isoforms. The final reaction in ubiquinone synthesis is a SAM-dependen Continue reading >>

Regulation Of Ketone Body And Coenzyme A

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 Contents…………………………………………………………………. iv List of Tables………………………………………………………………………. viii List of Figures……………………………………………………………………… ix Acknowledgements………………â Continue reading >>

We Really Can Make Glucose From Fatty Acids After All! O Textbook, How Thy Biochemistry Hast Deceived Me!

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 >>

Ketone Body Metabolism

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 >>

Cholesterol And Ketone Bodies Flashcards Preview

Cholesterol And Ketone Bodies Flashcards Preview

They are a second source of metabolic fuel. They are used in: The brain (75% of fuel in starvation conditions - in the absence of glucose) The heart and renal cortex (prefer ketone bodies over fatty acids and glucose) Skeletal muscle (can adapt to almost any fuel). Ketone bodies are synthesised in the mitochondria of hepatocytes. While low-level stimulus is constant, production is stimulated when OAA is diverted from the TCA cycle to gluconeogenesis (i.e. starvation conditions). 1. Two acetyl-CoA are condensed, with THIOLASE acting as the enzyme, forming ACETO-ACETYL-CoA, and spinning off one CoA (thiol group). 2. A third acetyl-CoA is added by HMG-CoA SYNTHASE, forming HMG-CoA, and spinning off another CoA. This step is a branch point for either ketone body or cholesterol synthase. 3. An acetyl-CoA is removed (spun off) by HMG-CoA LYASE, forming ACETO-ACETATE. This is a ketone body itself. 4. Aceto-acetate can be decarboxylated (CO2 removed) to form ACETONE. Or, it can be acted on by ß-HYDROXY-BUTYRATE-DEHYDROGENASE and NADH to form ß-HYDROXY-BUTYRATE. Ketone body catabolism is almost exactly the reverse of synthesis, however it cannot occur in the liver, due to the need of keto-acyl-CoA transferase, which is only found in peripheral tissue. 1. ß-Hydroxy-butyrate is acted on by ß-HYDROXY-BUTYRATE DEHYDROGENASE and NAD, producing ACETO ACETATE and NADH. 2. Aceto Acetate is acted on by KETO-ACYL-CoA-TRANSFERASE in the presence of succinyl-CoA. It removes the CoA from succinyl-CoA, and attaches it to the aceto-acetate, forming ACETO-ACETYL-CoA. (This is the step that cannot occur in the liver). 3. Aceto-acetyl-CoA undergoes thiolysis via THIOLASE, which adds an additional CoA (thiol) group, forming two Acetyl-CoA molecules that can enter the TCA cycle. Low levels of i Continue reading >>

Diabetes And Ketones

Diabetes And Ketones

Tweet The presence of high levels of ketones in the bloodstream is a common complication of diabetes, which if left untreated can lead to ketoacidosis. Ketones build up when there is insufficient insulin to help fuel the body’s cells. High levels of ketones are therefore more common in people with type 1 diabetes or people with advanced type 2 diabetes. If you are suffering from high levels of ketones and seeking medical advice, contact your GP or diabetes healthcare team as soon as possible. What are ketones? Ketones are an acid remaining when the body burns its own fat. When the body has insufficient insulin, it cannot get glucose from the blood into the body's cells to use as energy and will instead begin to burn fat. The liver converts fatty acids into ketones which are then released into the bloodstream for use as energy. It is normal to have a low level of ketones as ketones will be produced whenever body fat is burned. In people that are insulin dependent, such as people with type 1 diabetes, however, high levels of ketones in the blood can result from taking too little insulin and this can lead to a particularly dangerous condition known as ketoacidosis. How do I test for ketones? Ketone testing can be carried out at home. The most accurate way of testing for ketones is to use a blood glucose meter which can test for ketones as well as blood glucose levels. You can also test urine for ketone levels, however, the testing of urine means that the level you get is representative of your ketone levels up to a few hours ago. Read about testing for ketones and how to interpret the results Who needs to be aware of ketones? The following people with diabetes should be aware of ketones and the symptoms of ketoacidosis: Anyone dependent on insulin – such as all people Continue reading >>

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