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Ketogenesis Pathway

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 >>

Fatty Acid Oxidation And Ketogenesis

Fatty Acid Oxidation And Ketogenesis

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

Ketogenesis

Ketogenesis

What is Ketogenesis? Ketogenesis (1, 2) is a biochemical process that produces ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies the needed energy of certain organs, especially the brain. Not having enough ketogenesis could result to hypoglycaemia and over production of ketone bodies leading to a condition called ketoacidosis. It releases ketones when fat is broken down for energy. There are many ways to release ketones such as through urination and exhaling acetone. Ketones have sweet smell on the breath. (3) Ketogenesis and ketoacidosis are entirely different thing. Ketoacidosis is associated with diabetes and alcoholism, which could lead to even serious condition like kidney failure and even death. Picture 1 : Ketogenic pathway Photo Source : medchrome.com Image 2 : A pyramid of ketogenic diet Photo Source : www.healthline.com What are Ketone bodies? Ketone bodies are water soluble molecules produced by the liver from fatty acids during low food intake or fasting. They are also formed when the body experienced starvation, carbohydrate restrictive diet, and prolonged intense exercises. It is also possible in people with diabetes mellitus type 1. The ketone bodies are picked up by the extra hepatic tissues and will convert to acetyl-CoA. They will enter the citric acid cycle and oxidized in the mitochondria to be used as energy. Ketone bodies are needed by the brain to convert acetyl-coA into long chain fatty acids. Ketone bodies are produced in the absence of glucose. (1, 2, 3) It is easy to detect the presence of ketone bodies. Just observe the person’s breath. The smell of the breath is fruity and sometimes described as a nail polish remover-like. It depicts the presence of acetone or ethyl acetate. The ketone bodies includ 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. Continue reading >>

6 Health Benefits Of Ketogenesis And Ketone Bodies

6 Health Benefits Of Ketogenesis And Ketone Bodies

With heavy coverage in the media, ketogenic diets are all the rage right now. And for a good reason; for some people, they truly work. But what do all these different terms like ketogenesis and ketone bodies actually mean? Firstly, this article takes a look at what the ketogenesis pathway is and what ketone bodies do. Following this, it will examine six potential health benefits of ketones and nutritional ketosis. What is Ketogenesis? Ketogenesis is a biochemical process through which the body breaks down fatty acids into ketone bodies (we’ll come to those in a minute). Synthesis of ketone bodies through ketogenesis kicks in during times of carbohydrate restriction or periods of fasting. When carbohydrate is in short supply, ketones become the default energy source for our body. As a result, a diet to induce ketogenesis should ideally restrict carb intake to a maximum of around 50 grams per day (1, 2). Ketogenesis may also occur at slightly higher levels of carbohydrate intake, but for the full benefits, it is better to aim lower. When ketogenesis takes place, the body produces ketone bodies as an alternative fuel to glucose. This physiological state is known as ‘nutritional ketosis’ – the primary objective of ketogenic diets. There are various methods you can use to test if you are “in ketosis”. Key Point: Ketogenesis is a biological pathway that breaks fats down into a form of energy called ketone bodies. What Are Ketone Bodies? Ketone bodies are water-soluble compounds that act as a form of energy in the body. There are three major types of ketone body; Acetoacetate Beta-hydroxybutyrate Acetone (a compound created through the breakdown of acetoacetate) The first thing to remember is that these ketones satisfy our body’s energy requirements in the same w Continue reading >>

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 >>

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 >>

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 >>

Lipolysis And The Oxidation Of Fatty Acids

Lipolysis And The Oxidation Of Fatty Acids

Dietary lipids, in the form of triglycerides (triacylglycerides), phospholipids, and cholesterol, are digested by various lipases. The bulk of dietary lipids in the human diet are in the form of triglycerides. The lipases found in the gastrointestinal tract include one originally identified as lingual lipase (secreted by acinar cells of von Ebner glands of the tongue), gastric lipase (secreted by Chief cells of the stomach), pancreatic lipase (PNLIP gene), and pancreatic lipase-related protein 2 (PNLIPRP2 gene). These enzymes generate free fatty acids and a mixture of mono- and diglycerides from dietary triglycerides. Lingual lipase and gastric lipase are both derived from the lipase F, gastric (LIPF) gene and together constitute the acid lipases. The acidic lipases function essentially only in the acidic environment of the stomach. However, evidence suggests that lingual lipase functions within the mouth allowing for the ability to taste non-esterified fatty acids (NEFAs). The acid lipases are distinct from pancreatic lipases in that they do not require a lipid-bile acid interface for activity nor do they require the presence of the protein colipase. Pancreatic lipases, on the other hand, only function in the neutral pH environment generated in the small intestine by the secretion of pancreatic bicarbonate (HCO3–). Also, pancreatic lipases require the presence of colipase and a lipid-bile acid interface for their activity. The role of colipase in pancreatic lipase function is to anchor the lipase to the surface of an emulsified lipid droplet and to prevent it from being removed by bile salts. Pancreatic lipase degrades triglycerides at the sn-1 and sn-3 positions sequentially to generate 1,2-diacylglycerides (DAG) and 2-monoacylglycerides (MAG). Phospholipids are deg Continue reading >>

Question: What Purpose Does The Ketogenesis Pathway Serve For An Individual? Discuss Factors That Promote I...

Question: What Purpose Does The Ketogenesis Pathway Serve For An Individual? Discuss Factors That Promote I...

Excess sugar which has been taken through food in the form of carbohydrates gets stored in the form of liver glycogen and muscular glycogen. This excess liver glycogen gets converted into body fat. This body fat, liver and muscle glycogen stores get ... view the full answer Continue reading >>

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 >>

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 >>

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 >>

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

Metabolic reprogramming and metabolic rewiring have been used to describe the metabolic alterations in cancer cells where bioenergetics, anabolic biosynthesis and appropriate redox status are coordinated to promote cell proliferation and tumor growth. We believe that metabolic reprogramming represents software changes in cancer cells and describes metabolic alterations normally induced by growth factors in proliferative cells that are hijacked by oncogenic signals, whereas metabolic rewiring represents hardware changes in cancer cells and describes metabolic alterations that are newly forged due to neo-function of distinct oncogenic mutants, but not found in normal cells. Although increasing evidence emerges and suggests that different human cancers may share common metabolic properties, such as the Warburg effect, it is not clear whether distinct oncogene mutations, including oncogenes as well as tumor suppressor genes (TSGs), in different cancer types may require different metabolic properties for tumor development, and thus specifically rewire and reprogram cancer cell metabolism. We approached to this question by identifying unique metabolic vulnerability required by oncogenic BRAF V600E mutant in human melanoma cells, which are not required by other oncogenes such as NRas Q61R/K. We found that HMG-CoA lyase (HMGCL), a key enzyme in ketogenesis producing ketone bodies, is a synthetic lethal partner of BRAF V600E. HMGCL expression is upregulated in BRAF V600E-expressing human primary melanoma and hairy cell leukaemia cells in tissue samples from patients. Suppression of HMGCL specifically attenuates proliferation and tumor growth potential of human melanoma cells expressing BRAF V600E. Mechanistically, HMGCL controls the intracellular levels of its product, acetoacet 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.

Publication Type Journal Article Year of Publication 2015 Authors Kang, H-B, Fan, J, Lin, R, Elf, S, Ji, Q, Zhao, L, Jin, L, Seo, JHo, Shan, C, Arbiser, JL, Cohen, C, Brat, D, Miziorko, HM, Kim, E, Abdel-Wahab, O, Merghoub, T, Fröhling, S, Scholl, C, Tamayo, P, Barbie, DA, Zhou, L, Pollack, BP, Fisher, K, Kudchadkar, RR, Lawson, DH, Sica, G, Rossi, M, Lonial, S, Khoury, HJ, Khuri, FR, Lee, BH, Boggon, TJ, He, C, Kang, S, Chen, J Journal Mol Cell Volume 59 Issue 3 Pages 345-58 Date Published 2015 Aug 06 ISSN 1097-4164 Keywords Acetoacetates, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Hairy Cell, MAP Kinase Kinase 1, Melanoma, Mutation, Octamer Transcription Factor-1, Oxo-Acid-Lyases, Proto-Oncogene Proteins B-raf, Signal Transduction, Up-Regulation 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 " Continue reading >>

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