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.
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 >>
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 >>
Metabolic Rewiring By Oncogenic Braf V600e Links Ketogenesis Pathway To Braf-mek1 Signaling
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. Many cancers share common metabolic alterations, yet how such alterations contribute to tumor development remains unclear. Kang etal. demonstrate a "synthetic lethal" interaction between oncogenic BRAF V600E and a ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) that promotes BRAF V600E-dependent tumor development. Continue reading >>
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 >>
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 >>
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 >>
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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 >>
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 >>
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 >>
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 >>
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 >>
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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 >>
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 >>
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 >>
