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Ketogenesis Pathway

How Ketogenesis And Ketones Treat Inflammation

How Ketogenesis And Ketones Treat Inflammation

Intro Inflammation is a biological mechanism our bodies use to deal with internal and external events, such as combatting infections, repairing tissues or mitigating the immediate consequences of a fractured bone. However, it often carries a negative connotation since many diseases provoke symptoms through the process of inflammation. So although it is absolutely necessary for keeping the human body functioning properly, like so many things in biology, too much or too little is the problem. Inflammation can be managed with and without drugs. Here we will focus on ketogenesis and ketones with regards to treating inflammation since both drug and drug-free approaches can be discussed. What is ketogenesis? Ketogenesis is the process whereby your body produces molecules called ketone bodies, also known as ketones (see What’s a Ketone?). More specifically, ketogenesis is a series of biochemical reactions that builds molecules (ketones) from parts of other ones (like 2 acetyl-CoA molecules). How ketone bodies are formed? Fellow nerds can gaze upon the ketogenesis pathway below (1) whilst the non-initiated can simply keep in mind that our liver is ground-zero for ketogenesis. This is where fat is used as the raw material to produce 3 kinds of ketone bodies. Humans are remarkably good at ketogenesis. Just for comparison, dogs too can make ketones but the degree to which they require protein, carbohydrate or caloric restriction to do so is greater (2,3). Once you’ve produced enough ketones by upregulating ketogenesis, you eventually move into a metabolic state called ketosis. People are in ketosis when they are on a diet low enough in carbohydrates, known as a ketogenic diet, or when eating very very little if any food at all for example. What a ketogenic diet and fasting hav 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 >>

164 24.3 Lipid Metabolism

164 24.3 Lipid Metabolism

Learning Objectives By the end of this section, you will be able to: Explain how energy can be derived from fat Explain the purpose and process of ketogenesis Describe the process of ketone body oxidation Explain the purpose and the process of lipogenesis Fats (or triglycerides) within the body are ingested as food or synthesized by adipocytes or hepatocytes from carbohydrate precursors (Figure 1). 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 Figure 1b) 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 (Figure 2). The chylomicrons enable fats an Continue reading >>

Metabolic Pathways: How The Body Uses Energy

Metabolic Pathways: How The Body Uses Energy

Metabolic pathways in the body determine how we utilize the macronutrients (carbohydrates, proteins and fats) we eat, and ultimately what happens to the fuels that come from each macronutrient. It all depends on when the last meal was finished. If the body is in a "fasting or starvation" mode, energy pathways will behave differently than when food is available. Food is available! The macronutrients (carbohydrate, fats and protein) on your plate are broken down in separate metabolic pathways: Carbohydrates are broken down into glucose by various enzymes. Some are burned for immediate energy, but overall the level of glucose in the blood stream rises, which triggers an insulin release by the pancreas. The insulin acts to push glucose into the cells to be made into ATP, stored as glycogen or when in excess amounts, stored as fat droplets called triglycerides in the fat cells (adipose tissue). Fats are digested in the small intestine, and then packaged into lipoproteins for various functions (ever heard of LDL and HDL? ) Excess fat calories often end up as fat droplets in fat cells. When fats are used as an energy source, they are broken down in cellular mitochondria through a process called beta-oxidation. Proteins are broken down into individual amino acids and used in body cells to form new proteins or to join the amino acid pool, a sort of "cache" for these molecules. Amino acids that are in excess of the body's needs are converted by liver enzymes into keto acids and urea. Keto acids may be used as sources of energy, converted into glucose, or stored as fat. Urea is excreted from everyone’s body in sweat and urine. Body is "Fasting" Carbohydrate, fats and protein are metabolized in separate processes into a common product called acetyl-CoA. Acetyl-CoA is a major meta Continue reading >>

Article Metabolic Rewiring By Oncogenic Braf V600e Links Ketogenesis Pathway To Braf-mek1 Signaling

Article Metabolic Rewiring By Oncogenic Braf V600e Links Ketogenesis Pathway To Braf-mek1 Signaling

Highlights • • BRAF V600E upregulates HMGCL in human cancers • • Active BRAF upregulates HMGCL via Oct-1 Many human cancers share similar metabolic alterations, including the Warburg effect. However, it remains unclear whether oncogene-specific metabolic alterations are required for tumor development. Here we demonstrate a “synthetic lethal” interaction between oncogenic BRAF V600E and a ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL). HMGCL expression is upregulated in BRAF V600E-expressing human primary melanoma and hairy cell leukemia cells. Suppression of HMGCL specifically attenuates proliferation and tumor growth potential of human melanoma cells expressing BRAF V600E. Mechanistically, active BRAF upregulates HMGCL through an octamer transcription factor Oct-1, leading to increased intracellular levels of HMGCL product, acetoacetate, which selectively enhances binding of BRAF V600E but not BRAF wild-type to MEK1 in V600E-positive cancer cells to promote activation of MEK-ERK signaling. These findings reveal a mutation-specific mechanism by which oncogenic BRAF V600E “rewires” metabolic and cell signaling networks and signals through the Oct-1-HMGCL-acetoacetate axis to selectively promote BRAF V600E-dependent tumor development. Graphical Abstract Continue reading >>

Metabolic Rewiring By Oncogenic Braf V600e Links Ketogenesis Pathway To Braf-mek1 Signaling

Metabolic Rewiring By Oncogenic Braf V600e Links Ketogenesis Pathway To Braf-mek1 Signaling

Abstract Many human cancers share similar metabolic alterations, including the Warburg effect. However, it remains unclear whether oncogene-specific metabolic alterations are required for tumor development. Here we demonstrate a "synthetic lethal" interaction between oncogenic BRAF V600E and a ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL). HMGCL expression is upregulated in BRAF V600E-expressing human primary melanoma and hairy cell leukemia cells. Suppression of HMGCL specifically attenuates proliferation and tumor growth potential of human melanoma cells expressing BRAF V600E. Mechanistically, active BRAF upregulates HMGCL through an octamer transcription factor Oct-1, leading to increased intracellular levels of HMGCL product, acetoacetate, which selectively enhances binding of BRAF V600E but not BRAF wild-type to MEK1 in V600E-positive cancer cells to promote activation of MEK-ERK signaling. These findings reveal a mutation-specific mechanism by which oncogenic BRAF V600E "rewires" metabolic and cell signaling networks and signals through the Oct-1-HMGCL-acetoacetate axis to selectively promote BRAF V600E-dependent tumor development. Copyright © 2015 Elsevier Inc. All rights reserved. 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 >>

What Is Gluconeogenesis?

What Is Gluconeogenesis?

Eat fat burn fat. Eat carbs burn carbs. It’s that simple, right? Yes and no. There’s more to it. Your body has many different metabolic pathways that it uses to provide energy for your cells. Glycolysis (using sugar for fuel) and lipolysis (using fat for fuel through beta-oxidation) are the most well-known metabolic pathways, but there are many more. One pathway, in particular, can turn the amino acids from protein into fuel. Why does it matter? Because this may be the one thing that is holding you back from getting into ketosis and losing fat while you are on a ketogenic diet. Gluconeogenesis — Your Liver’s “Magic Trick” If you are under some form stress or consume excess protein, your liver will perform a magic trick called gluconeogenesis. This literally translates to “the making of (genesis) new (neo) sugar (gluco)”. During gluconeogenesis, the liver (and occasionally the kidneys) turns non-sugar compounds like amino acids (the building blocks of protein), lactate, and glycerol into sugar that the body uses a fuel. When glycogen (your body’s sugar storage) is low, protein intake is high, or the body is under stress, amino acids from your meals and your muscle become one of your main energy sources. If your body continues to convert amino acids into fuel, it can keep you from getting into ketosis. This is why some ketogenic dieters may experience an increase in body fat percentage and a decrease in muscle mass during their first couple weeks on the ketogenic diet. But there is no need to worry. The ketogenic diet will still help reverse common health issues like diabetes and obesity and improve health in many ways. When you start the diet, however, gluconeogenesis will get in the way. One of the Problems With Going Ketogenic During the first three d Continue reading >>

Utilization Of Ketone Bodies, Regulation And Clinical Significance Of Ketogenesis

Utilization Of Ketone Bodies, Regulation And Clinical Significance Of Ketogenesis

Ketone bodies are utilized by extra hepatic tissues via a series of cytosolic reactions that are essentially a reversal of ketone body synthesis; the ketones must be reconverted to acetyl Co A in the mitochondria (figure-1) Steps 1) Utilization of β-Hydroxy Butyrate Beta-hydroxybutyrate is first oxidized to acetoacetate with the production of one NADH (Figure-1, step-1). In tissues actively utilizing ketones for energy production, NAD+/NADH ratio is always higher so as to drive the β-hydroxybutyrate dehydrogenase catalyzed reaction in the direction of acetoacetate synthesis. Biological significance D (-)-3-Hydroxybutyrate is oxidized to produce acetoacetate as well as NADH for use in oxidative phosphorylation. D (-)-3-Hydroxybutyrate is the main ketone body excreted in urine. 2) Utilization of Acetoacetate a) Coenzyme A must be added to the acetoacetate. The thioester bond is a high energy bond, so ATP equivalents must be used. In this case the energy comes from a trans esterification of the CoASH from succinyl CoA to acetoacetate by Coenzyme A transferase (Figure-1, step-2), also called Succinyl co A: Acetoacetate co A transferase, also known as Thiophorase. The Succinyl CoA comes from the TCA cycle. This reaction bypasses the Succinyl-CoA synthetase step of the TCA cycle; hence there is no GTP formation at this step although it does not alter the amount of carbon in the cycle. Biological significance The liver has acetoacetate available to supply to other organs because it lacks this particular CoA transferase and that is the reason “Ketone bodies are synthesized in the liver but utilized in the peripheral tissues”. The latter enzyme is present at high levels in most tissues except the liver. Importantly, very low-level of enzyme expression in the liver allows t Continue reading >>

Ketogenesis

Ketogenesis

Ketogenesis pathway. The three ketone bodies (acetoacetate, acetone, and beta-hydroxy-butyrate) are marked within an orange box Ketogenesis is the biochemical process by which organisms produce a group of substances collectively known as ketone bodies by the breakdown of fatty acids and ketogenic amino acids.[1][2] This process supplies energy to certain organs (particularly the brain) under circumstances such as fasting, but insufficient ketogenesis can cause hypoglycemia and excessive production of ketone bodies leads to a dangerous state known as ketoacidosis.[3] Production[edit] Ketone bodies are produced mainly in the mitochondria of liver cells, and synthesis can occur in response to an unavailability of blood glucose, such as during fasting.[3] Other cells are capable of carrying out ketogenesis, but they are not as effective at doing so.[4] Ketogenesis occurs constantly in a healthy individual.[5] Ketogenesis takes place in the setting of low glucose levels in the blood, after exhaustion of other cellular carbohydrate stores, such as glycogen.[citation needed] It can also take place when there is insufficient insulin (e.g. in type 1 (but not 2) diabetes), particularly during periods of "ketogenic stress" such as intercurrent illness.[3] The production of ketone bodies is then initiated to make available energy that is stored as fatty acids. Fatty acids are enzymatically broken down in β-oxidation to form acetyl-CoA. Under normal conditions, acetyl-CoA is further oxidized by the citric acid cycle (TCA/Krebs cycle) and then by the mitochondrial electron transport chain to release energy. However, if the amounts of acetyl-CoA generated in fatty-acid β-oxidation challenge the processing capacity of the TCA cycle; i.e. if activity in TCA cycle is low due to low amo Continue reading >>

Regulation Of Ketone Body Metabolism And The Role Of Pparα

Regulation Of Ketone Body Metabolism And The Role Of Pparα

1. Introduction Adaptation to limited nutritional resources in the environment requires the development of mechanisms that enable temporal functioning in a state of energy deficiency at both systemic and cellular levels. Different molecular and cellular mechanisms have evolved allowing survival during nutrient insufficiency. Some rely on the decrease of metabolic rates, body temperature, or even shutting down most of the live functions during deep hibernation, aestivation or brumation. Other strategies require development of metabolic flexibility and effective fuel management. Peroxisome Proliferator Activated Receptors (PPARs) are important regulators of cellular responses to variable nutrient supply during both fed and fasted states. Acting as transcription factors, and directly modulated by fatty acids and their derivatives, PPARs induce transcription of the proper set of genes, encoding proteins and enzymes indispensable for lipid, amino acid and carbohydrate metabolism. In this review, we make an attempt to outline the regulation of ketone body synthesis and utilization in normal and transformed cells, as well as summarize the role of PPARα in these processes. 2. Ketogenesis and Ketolysis Metabolic adaptation to prolonged fasting in humans is based both on coordinated responses of vital organs, mainly liver, kidneys and muscles, and on restoring nutritional preferences at the cellular level. In the fed state, cells primarily rely on glucose metabolism, whereas during longer food deprivation blood glucose levels drop because glycogen reserves are only sufficient for less than a day. In such conditions, glucose is spared mainly for neurons, but also for erythrocytes and proliferating cells in bone marrow or those involved in tissue regeneration. The most important c 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 >>

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 >>

Ketone Bodies Metabolism

Ketone Bodies Metabolism

1. Metabolism of ketone bodies Gandham.Rajeev Email:[email protected] 2. • Carbohydrates are essential for the metabolism of fat or FAT is burned under the fire of carbohydrates. • Acetyl CoA formed from fatty acids can enter & get oxidized in TCA cycle only when carbohydrates are available. • During starvation & diabetes mellitus, acetyl CoA takes the alternate route of formation of ketone bodies. 3. • Acetone, acetoacetate & β-hydroxybutyrate (or 3-hydroxybutyrate) are known as ketone bodies • β-hydroxybutyrate does not possess a keto (C=O) group. • Acetone & acetoacetate are true ketone bodies. • Ketone bodies are water-soluble & energy yielding. • Acetone, it cannot be metabolized 4. CH3 – C – CH3 O Acetone CH3 – C – CH2 – COO- O Acetoacetate CH3 – CH – CH2 – COO- OH I β-Hydroxybutyrate 5. • Acetoacetate is the primary ketone body. • β-hydroxybutyrate & acetone are secondary ketone bodies. • Site: • Synthesized exclusively by the liver mitochondria. • The enzymes are located in mitochondrial matrix. • Precursor: • Acetyl CoA, formed by oxidation of fatty acids, pyruvate or some amino acids 6. • Ketone body biosynthesis occurs in 5 steps as follows. 1. Condensation: • Two molecules of acetyl CoA are condensed to form acetoacetyl CoA. • This reaction is catalyzed by thiolase, an enzyme involved in the final step of β- oxidation. 7. • Acetoacetate synthesis is appropriately regarded as the reversal of thiolase reaction of fatty acid oxidation. 2. Production of HMG CoA: • Acetoacetyl CoA combines with another molecule of acetyl CoA to produce β-hydroxy β-methyl glutaryl CoA (HMC CoA). • This reaction is catalyzed by the enzyme HMG CoA synthase. 8. • Mitochondrial HMG CoA is used for ketogenesis. Continue reading >>

Lipid Metabolism And Ketogenesis

Lipid Metabolism And Ketogenesis

With Picmonic, facts become pictures. We've taken what the science shows - image mnemonics work - but we've boosted the effectiveness by building and associating memorable characters, interesting audio stories, and built-in quizzing. Lips with Metal-balls and Key-genie Picmonic Lipid metabolism is composed of catabolic processes that generate energy and anabolic processes that create biologically important molecules, such as triglycerides, phospholipids, second messengers, local hormones and ketone bodies. Ketogenesis is the process of breaking down fatty acids in order to produce ketone bodies, such as acetoacetate, acetone, and beta-hydroxybutyrate. Picmonic for Medicine (MD/DO) covers information that is relevant to your entire Medical (MD/DO) education. Whether you’re studying for your classes or getting ready to conquer the USMLE Step 1, USMLE Step 2 CK, COMLEX Level 1, or COMLEX Level 2, we’re here to help. Research shows that students who use Picmonic see a 331% improvement in memory retention and a 50% improvement in test scores. "[Picmonics] correlate directly with what is in First Aid so you know it is essential information that will show up on the exam. The number of questions I got right in biochemistry and microbiology were mainly due to this resource." James, Texas Tech University Health Sciences Center School of Medicine, 274 on Step 1 TRY IT FREE Continue reading >>

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