ketosis

Information about ketosis

Published on October 14, 2014

Author: drmustansar

Source: authorstream.com

Content

PowerPoint Presentation: 10/14/2014 1 KETOSIS- CAUSES AND CONSEQUENCES: KETOSIS- CAUSES AND CONSEQUENCES 10/14/2014 Biochemistry For Medics 2 Ketone Bodies: Ketone Bodies Ketone bodies can be regarded as water-soluble , transportable form of acetyl units. Fatty acids are released by adipose tissue and converted into acetyl units by the liver, which then exports them as ketone bodies. Acetoacetate, D(-3) –hydroxy butyrate (Beta hydroxy butyrate), and acetone are often referred to as  ketone bodies   10/14/2014 Biochemistry For Medics 3 PowerPoint Presentation: 10/14/2014 Biochemistry For Medics 4 Ketogenesis: Ketogenesis Ketogenesis takes place in liver using Acetyl co A as a substrate or a precursor molecule . Enzymes responsible for ketone body formation are associated mainly with the mitochondria Steps Two molecules of acetyl CoA condense to form acetoacetyl CoA. This reaction, which is catalyzed by  thiolase , is the reverse of the thiolysis step in the oxidation of fatty acids . 10/14/2014 Biochemistry For Medics 5 Ketogenesis: Ketogenesis Acetoacetyl CoA then reacts with acetyl CoA and water to give 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) and CoASH . The reaction is catalyzed by HMG co A synthase.  This enzyme is exclusively present in liver mitochondria. There are two isoforms of this enzyme-cytosolic and mitochondrial.  The mitochondrial enzyme is needed for ketogenesis while the cytosolic form is associated with cholesterol biosynthesis. 10/14/2014 Biochemistry For Medics 6 Ketogenesis: Ketogenesis This condensation resembles the one catalyzed by citrate synthase. This reaction, which has a  favorable equilibrium owing to the hydrolysis of a thioester linkage, compensates for the unfavorable equilibrium in the formation of acetoacetyl CoA. 3-Hydroxy-3-methylglutaryl CoA is then cleaved to acetyl CoA and acetoacetate in the presence of HMG Co A  lyase . The carbon atoms split off in the acetyl-CoA molecule are derived from the original Acetoacetyl -CoA molecule.  10/14/2014 Biochemistry For Medics 7 PowerPoint Presentation: 10/14/2014 Biochemistry For Medics 8 Ketogenesis: Ketogenesis Both enzymes(HMG CoA Synthase and HMG Co A Lyase ) must be present in mitochondria for ketogenesis to take place.  This occurs solely in liver and rumen epithelium, The sum of these reactions is- The other two ketone bodies-Acetone and D(-)- 3-Hydroxybutyrate  are formed from Acetoacetate, the primary ketone body. 10/14/2014 Biochemistry For Medics 9 Formation of Acetone: Formation of Acetone Acetone is formed by decarboxylation in the presence of decarboxylase enzyme and, because it is a beta-keto acid, acetoacetate also undergoes a slow, spontaneous decarboxylation to acetone. The odor of acetone may be detected in the breath of a person who has a high level of acetoacetate in the blood.   “ Acetone-breath” has been used as   a   crude   method of  diagnosing  individuals  with  untreated Type I diabetes mellitus. 10/14/2014 Biochemistry For Medics 10 Formation of β-Hydroxy Butyrate: Formation of β -Hydroxy Butyrate   D (-)- 3-Hydroxybutyrate ( β -Hydroxy Butyrate) is formed by the reduction of acetoacetate in the mitochondrial matrix by D(-)3-hydroxybutyrate dehydrogenase. D (-)-3-Hydroxybutyrate is quantitatively the predominant ketone body present in the blood and urine in ketosis. The β- hydroxybutyrate dehydrogenase reaction has two functions: 1) it stores energy equivalent to an NADH in the ketone body for export to the tissues, and  2) it  produces  a  more  stable molecule . The ratio of β hydroxybutyrate to acetoacetate depends on the NADH/NAD+ ratio inside mitochondria. If NADH concentration is high, the liver releases a higher proportion of β- hydroxybutyrate. 10/14/2014 Biochemistry For Medics 11 Why are three enzymes required to synthesize acetoacetate?: Why are three enzymes required to synthesize acetoacetate? An enzyme that cleaves the thioester  bond of the thiolase   product  acetoacetyl -CoA  would  also produce acetoacetate, but such a thioesterase does not seem to exist. However , the pathway that does exist is not especially wasteful; the third acetyl-CoA used merely acts catalytically Because the cell needs to have HMG-CoA synthase for other purposes, the choice is in having HMG-CoA lyase It is possible that having two mitochondrial enzymes (HMG-CoA synthase and HMG-CoA lyase ) required for ketone body synthesis assists in controlling the pathway. 10/14/2014 Biochemistry For Medics 12 Utilization of ketone bodies: Utilization of ketone bodies   Ketone bodies serve as a fuel for extra hepatic tissues The ketone bodies are water soluble and are transported across the inner mitochondrial membrane as well as across the blood-brain barrier and cell membranes. T hey can be used as a fuel source by a variety of tissues including the CNS . They are preferred substrates for aerobic muscle and heart, thus sparing glucose when they are available. Tissues that can use fatty acids can generally use ketone bodies in addition to other energy sources . The exceptions are the liver and the brain.  10/14/2014 Biochemistry For Medics 13 Utilization of ketone bodies: Utilization of ketone bodies Ketone bodies are utilized by extrahepatic tissues via a series of cytosolic reactions that are essentially a reversal of ketone body synthesis, the ketones must be reconverted to acetyl CoA in the mitochondria : Utilization of Beta -hydroxybutyrate Beta -hydroxybutyrate, is first oxidized to acetoacetate with the production of one NADH  (1) . Under conditions where tissues are utilizing ketones for energy production their NAD + /NADH ratios are going to be relatively high, thus driving the β-hydroxybutyrate dehydrogenase catalyzed reaction in the direction of acetoacetate synthesis.  10/14/2014 Biochemistry For Medics 14 Utilization of ketone bodies: Utilization of ketone bodies 2) 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 CoAS from Succinyl CoA to acetoacetate by Coenzyme A transferase, 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 steps although it does not alter the amount of carbon in the cycle. 10/14/2014 Biochemistry For Medics 15 Utilization of ketone bodies: Utilization of ketone bodies The liver has acetoacetate available to supply to other organs because it lacks the particular CoA transferase and that is the reason that “Ketone bodies are synthesized in the liver but utilized in the peripheral tissues”.   10/14/2014 Biochemistry For Medics 16 Liver v/s Peripheral tissues for ketones as fuel molecules: Liver v/s Peripheral tissues for ketones as fuel molecules The enzyme , Succniyl co A Acetoacetate co A transferase, also known as Thiophorase, is present at high levels in most tissues except the liver. Importantly, very low level of enzyme expression in the liver allows the liver to produce ketone bodies but not to utilize them. This ensures that extra hepatic tissues have access to ketone bodies as a fuel source during prolonged fasting and starvation, and Also, lack of this enzyme in the liver prevents the futile cycle of synthesis and breakdown of acetoacetate . 10/14/2014 Biochemistry For Medics 17 Regulation of Ketosis: Regulation of Ketosis Ketogenesis is regulated at three steps- 1) Lipolysis in Adipose tissue Ketosis does not occur unless there is an increase in the level of circulating free fatty acids that arise from lipolysis of triacylglycerol in adipose tissue. When glucose levels fall, lipolysis induced by glucagon secretion causes increased hepatic ketogenesis due to increased substrate (free fatty acids) delivery from adipose tissue. Conversely, insulin, released in the well-fed state, inhibits ketogenesis via the triggering dephosphorylation and inactivation of adipose tissue hormone sensitive lipase (HSL). 10/14/2014 Biochemistry For Medics 18 Lipolysis in Adipose tissue : Lipolysis in Adipose tissue Hormone sensitive lipase exists in two forms inactive dephosphorylated (brought by Insulin) and active phosphorylated form (brought by glucagon, ACTH and catecholamines). Insulin promotes lipogenesis while the other hormones  promote lipolysis. 10/14/2014 Biochemistry For Medics 19 Regulation of Ketosis: Regulation of Ketosis 2) Fate of fatty acid- free fatty acids are either  oxidized  to CO 2  or ketone bodies or  esterified to triacylglycerol and phospholipids.  There is regulation of entry of fatty acids into the oxidative pathway by  carnitine Acyl transferase-I  (CAT-I) Malonyl-CoA, the initial intermediate in fatty acid biosynthesis formed by acetyl-CoA carboxylase in the fed state, is a potent inhibitor of CAT-I . Under these conditions, free fatty acids enter the liver cell in low concentrations and are nearly all esterified to acylglycerols and transported out of the liver in very low density lipoproteins (VLDL). 10/14/2014 Biochemistry For Medics 20 Regulation of CAT-1 activity: Regulation of CAT-1 activity CAT-I activity is low in the fed state, leading to depression of fatty acid oxidation. However, CAT-1 activity is higher in starvation, allowing fatty acid oxidation to increase. 10/14/2014 Biochemistry For Medics 21 Regulation of Ketosis: Regulation of Ketosis 3) Fate of Acetyl co A  The acetyl-CoA formed in  beta-oxidation is oxidized in the citric acid cycle, or it enters the pathway of ketogenesis to form ketone bodies. As the level of serum free fatty acids is raised, proportionately more free fatty acids are  converted to ketone bodies and less are oxidized via the citric acid cycle to CO 2 . Entry of acetyl CoA into the citric acid cycle depends on the availability of Oxaloacetate for the formation of citrate, but the concentration of Oxaloacetate is lowered if carbohydrate is unavailable or improperly utilized.  10/14/2014 Biochemistry For Medics 22 Regulation of Ketosis- Overview: Regulation of Ketosis- Overview During high rates of fatty acid oxidation, primarily in the liver, large amounts of acetyl-Co A are generated. These exceed the capacity of the TCA cycle, and one result is the synthesis of ketone bodies.  10/14/2014 Biochemistry For Medics 23 Biological significance of ketone bodies: Biological significance of ketone bodies Ketone bodies serve as a fuel for extra hepatic tissues Brain   It  is  metabolically  active  and  metabolically privileged. The brain generally uses 60-70% of total body glucose requirements, and always  requires  some  glucose for  normal  functioning.  Under  most  conditions, glucose is essentially the sole energy source of the brain. The brain cannot use fatty acids as they cannot cross  the  blood-brain  barrier. As glucose availability decreases, the brain is forced to use either amino acids or ketone bodies for fuel. 10/14/2014 Biochemistry For Medics 24 Biological significance of ketone bodies: Biological significance of ketone bodies Acetoacetate and β-hydroxybutyrate are normal fuels of respiration and are quantitatively important as sources of energy . Heart muscle and the renal cortex use acetoacetate in preference to glucose. In contrast, the brain adapts to the utilization of acetoacetate during starvation and diabetes. In prolonged starvation,75% of the fuel needs of the brain are met by ketone bodies. Individuals eating diets extremely high in fat and low in carbohydrate, or starving, or suffering  from  a severe lack of insulin (Type I diabetes  mellitus) therefore increase the synthesis and utilization of ketone bodies 10/14/2014 Biochemistry For Medics 25 Ketonemia: Ketonemia Ketonemia - increased concentration of ketone bodies in blood It is due to increased production of ketone bodies  by the liver rather than to a deficiency in their utilization by extra hepatic tissues. The production of ketone bodies occurs at a relatively low rate during normal feeding and under conditions of normal physiological status.  Normal physiological responses to carbohydrate shortages cause the liver to increase the production of ketone bodies from the acetyl-CoA generated from fatty acid oxidation. 10/14/2014 Biochemistry For Medics 26 Causes of Ketosis: Causes of Ketosis Uncontrolled diabetes mellitus Starvation Chronic alcoholism Von- Gierke’s disease Heavy exercise Low carbohydrate diet- For weight loss Glycogen storage disease type 6(Due to phosphorylase kinase deficiency) Pyruvate carboxylase deficiency 10/14/2014 Biochemistry For Medics 27 Causes of Ketosis: Causes of Ketosis Prolonged ether anesthesia Toxemia of pregnancy Certain conditions of alkalosis  Nonpathologic forms of ketosis  are found under conditions of high-fat feeding and After severe exercise in the post absorptive state. 10/14/2014 Biochemistry For Medics 28 Clinical Significance-Ketoacidosis: Clinical Significance-Ketoacidosis Both β-hydroxybutyrate and acetoacetate are organic acids. and are released in the protonated form, to lower the pH of the blood. In  normal  individuals, other mechanisms compensate  for  the increased proton release. When  ketone bodies are released in large  quantities the normal  pH-buffering mechanisms are overloaded ; the reduced pH, in combination with a number of other metabolic  abnormalities  results in ketoacidosis. In severe ketoacidosis, cells begin to lose ability to use ketone bodies also. 10/14/2014 Biochemistry For Medics 29 Starvation induced ketosis: Starvation induced ketosis Prolonged fasting may result From an inability to obtain food from the desire to lose weight rapidly, or in clinical situations in which an individual cannot eat because of trauma, surgery, neoplasms, burns etc. In the absence of food the plasma levels of glucose, amino acids and triacylglycerols fall, triggering a decline in insulin secretion and an increase in glucagon release . 10/14/2014 Biochemistry For Medics 30 Starvation induced ketosis: Starvation induced ketosis The decreased insulin to glucagon ratio, makes this period of nutritional deprivation  a catabolic state , characterized by degradation of glycogen, triacylglycerol and protein. This sets in to motion an exchange of substrates between liver, adipose tissue, muscle and brain that is guided by two priorities- ( i ) the need to maintain glucose level to sustain the energy metabolism of brain ,red blood cells and other glucose requiring cells and (ii) to supply energy to other tissues by mobilizing fatty acids from adipose tissues and converting them to ketone bodies to supply energy to other cells of the body. 10/14/2014 Biochemistry For Medics 31 Starvation induced ketosis: Starvation induced ketosis In early stages of starvation , heart and skeletal muscle consume primarily ketone bodies to preserve glucose for use by the brain.  After several weeks of starvation, ketone bodies become the major fuel of the brain.  10/14/2014 Biochemistry For Medics 32 Diabetic Keto- acidosis : Diabetic Keto- acidosis Diabetic Ketoacidosis (DKA) is a state of inadequate insulin levels resulting in high blood sugar and accumulation of organic acids and ketones in the blood. It is a potentially life-threatening complication. It happens predominantly in type 1 diabetes mellitus, But can also occur in type 2 diabetes mellitus under certain circumstances. This may be due to intercurrent illness  (pneumonia, influenza, gastroenteritis, a urinary tract infection),  pregnancy, inadequate insulin administration  (e.g. defective insulin pen device),  myocardial infarction  (heart attack),  stroke  or the use of cocaine. Young patients with recurrent episodes of DKA may have an  underlying eating disorder , or may be using insufficient insulin for fear that it will cause weight gain. In 5% of cases, no cause for the DKA episode is found. 10/14/2014 Biochemistry For Medics 33 Diabetic Keto- acidosis : Diabetic Keto- acidosis DKA results from  relative or absolute insulin deficiency  combined with  counter regulatory hormone excess ( Glucagon, Catecholamines, cortisol, and growth hormone). The  decreased ratio of insulin to Glucagon  promotes Gluconeogenesis, glycogenolysis, and Ketone body formation  in the liver, as well as  increases in substrate delivery from fat and muscle  (free fatty acids, amino acids) to the liver The ketone bodies have a low pH and therefore cause metabolic acidosis. The body initially buffers these with the bicarbonate buffering system, and other mechanisms to compensate for the acidosis, such as hyperventilation to lower the blood carbon dioxide levels. This hyperventilation, in its extreme form, may be observed as  Kussmaul respiration . Ketones, too, participate in  osmotic diuresis  and lead to further electrolyte lo sses 10/14/2014 Biochemistry For Medics 34 Diabetic Keto- acidosis : Diabetic Keto- acidosis Diabetic Ketoacidosis may be diagnosed when the combination of  hyperglycemia (high blood sugars), ketones on urinalysis and acidosis are demonstrated.  10/14/2014 Biochemistry For Medics 35 Alcoholic ketoacidosis(AKA): Alcoholic ketoacidosis(AKA) Although the general physiological factors and mechanisms leading to AKA are understood, the precise factors have not been fully defined. The following are the 3 main predisposing events: Delay and decrease in insulin secretion and excess glucagon secretion, induced by starvation Elevated ratio of the reduced form of nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide (NAD + ) secondary to alcohol metabolism Volume depletion resulting from vomiting and poor oral intake of fluids 10/14/2014 Biochemistry For Medics 36 Alcoholic ketoacidosis(AKA): Alcoholic ketoacidosis(AKA) The metabolism of alcohol itself is a probable contributor to the ketotic state. Alcohol dehydrogenase metabolizes alcohol to acetaldehyde in the cytoplasm of hepatocyte mitochondria. Acetaldehyde is metabolized further to acetic acid by aldehyde dehydrogenase. Both steps require the reduction of nicotinamide adenine dinucleotide (NAD + ) to reduced nicotinamide adenine dinucleotide (NADH). Thus, NAD +  is consumed and NADH is generated. 10/14/2014 Biochemistry For Medics 37 Alcoholic ketoacidosis(AKA): Alcoholic ketoacidosis(AKA) The decreased ratio of NAD +  to NADH has the following implications: Impaired conversion of lactate to pyruvate with an increase in serum lactic acid levels Impaired gluconeogenesis because pyruvate is not available as a substrate for glucose production A shift in the hydroxybutyrate (β-OH) to acetoacetate ( AcAc ) equilibrium toward β-OH butyrate In contrast to diabetic ketoacidosis, the predominant ketone body in AKA is β-OH. Routine clinical assays for ketonemia test for AcAc and acetone but not for β-OH. Clinicians underestimate the degree of ketonemia if they rely solely on the results of laboratory testing. 10/14/2014 Biochemistry For Medics 38 Alcoholic ketoacidosis(AKA): Alcoholic ketoacidosis(AKA) Prolonged vomiting leads to dehydration, which decreases renal perfusion, thereby limiting urinary excretion of ketoacids . Moreover, volume depletion increases the concentration of counter-regulatory hormones, further stimulating lipolysis and ketogenesis. The pivotal variable appears to be a relative deficiency of insulin. Individuals with higher insulin levels are more likely to present with the syndrome of alcohol-induced hypoglycemia without ketoacidosis 10/14/2014 Biochemistry For Medics 39 Alcoholic ketoacidosis(AKA): Alcoholic ketoacidosis(AKA) Most cases of AKA occur when a person with poor nutritional status due to long-standing alcohol abuse who has been on a drinking binge suddenly decreases energy intake because of abdominal pain, nausea, or vomiting. In addition, AKA is often precipitated by another medical illness such as infection or pancreatitis. AKA results from the accumulation of the ketoacids , hydroxybutyric acid, and acetoacetic acid . Such accumulation is caused by the complex interaction stemming from alcohol cessation, decreased energy intake, volume depletion, and the metabolic effects of hormonal imbalance. 10/14/2014 Biochemistry For Medics 40 Summary: Summary The ketone bodies (acetoacetate, 3-hydroxybutyrate, and acetone) are formed in hepatic mitochondria when there is a high rate of fatty acid oxidation. The pathway of ketogenesis involves synthesis and breakdown of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by two key enzymes, HMG-CoA synthase and HMG-CoA lyase . Ketone bodies are important fuels in extrahepatic tissues. Ketogenesis is regulated at three crucial steps: (1) control of free fatty acid mobilization from adipose tissue; (2) the activity of carnitine acyl ltransferase -I in liver, which determines the proportion of the fatty acid flux that is oxidized rather than esterified; and (3) partition of acetyl-CoA between the pathway of ketogenesis and the citric acid cycle. 10/14/2014 Biochemistry For Medics 41

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