Ketogenesis

At the same time, ketogenesis, i.east. the product by the liver of the ketone bodies β-hydroxybutyrate and acetoacetate (AcAc), is a physiologically of import procedure to produce an alternative metabolic source of free energy during the neonatal period, starvation or prolonged physical endeavour [thirty].

From: Nutritional Epigenomics , 2019

Inborn Errors of Metabolism and the Nervous System

Joseph Jankovic Medico , in Bradley and Daroff's Neurology in Clinical Do , 2022

Disorders of Ketogenesis and Ketolysis

Excess acetyl-CoA, a by-product of FAO, is converted in hepatic tissue to the principal KB, 3-hydroxybutyrate and acetoacetate, which are transported to peripheral tissues for further metabolism. Ketone utilization past the brain spares glucose for utilise past other tissues, such as erythrocytes, the latter unable to meet their energy requirements from nonglucose substrates. In liver, condensation of acetyl-CoA occurs sequentially through the enzymes thiolase, three-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase, and HMG-CoA lyase. The latter is the final enzyme offifty-leucine metabolism, making this amino acrid a "ketogenic" amino acid.

The primary disorders of ketogenesis and ketolysis are rare, and include constructed disorders (HMG-CoA synthase and lyase deficiencies) and disorders of ketone utilization, including 3-oxothiolase deficiency (also β-ketothiolase deficiency, on the l-isoleucine catabolic pathway) in addition to succinyl-CoA:3-ketoacid transferase (SCOT) deficiency (Fukao et al., 2014). Synthetic disorders prominently feature hypoketotic hypoglycemia (as expected for defects limiting KB formation). When unchecked, three-oxothiolase deficiency features a prominent ketoacidosis, and is responsive to intravenous glucose. SCOT deficiency manifests permanent, unrelenting ketosis, a highly suggestive marker. SCOT may non exist reliably diagnosed by NBS.

Acetate

Martin Kohlmeier , in Nutrient Metabolism, 2003

Metabolism

Acetate can be utilized by muscle and other peripheral tissues (Pouteau et al., 1996). Complete oxidation of acetate requires thiamin, riboflavin, niacin, pantothenate, lipoate, ubiquinone, iron, and magnesium.

Commencement, free acetate must be conjugated to coenzyme A by acetate-CoA ligase (thiokinase; EC6.two.1.i). Nigh acetyl-CoA is utilized in mitochondria via the tricarboxylic acrid (Krebs) cycle. Citrate synthase (EC4.1.3.7) joins acetyl CoA to oxaloacetate. The citrate from this reaction tin so be metabolized further providing FADH, NADH, and succinate for oxidative phosphorylation and ATP or GTP from succinyl CoA.

The production charge per unit of acetyl-CoA from fatty acrid beta-oxidation in the liver with prolonged fasting usually exceeds the capacity of the Krebs cycle. The coenzyme A for continued beta-oxidation and other functions can be released through the production of acetoacetate in three steps. The typical odor of a fasting individual is partially related to exhaled acetone formed from acetoacetate. The conversion of acetoacetate into beta-hydroxybutyrate taxes the body'due south acrid-buffering capacity and may cause a drop in blood pH (acidosis) in diabetics and similarly susceptible patients. None of these events is related to dietary intake of acetate.

Ketogenesis takes place in the mitochondria where fatty acid catabolism generates acetyl-CoA. Acetyl-CoA C-acetyltransferase (thiolase; EC2.iii.1.nine) joins two acetyl-CoA molecules, and hydroxymethylglutaryl-CoA synthase (HMG-CoA synthase; EC4.1.3.five) adds another one. The mitochondrial isoform of HMG-CoA synthase is genetically distinct from the cytosolic one, which generates the precursor for cholesterol synthesis. Hydroxymethylglutaryl-CoA lyase (HMG-CoA lyase, EC4.i.3.4) finally generates acetoacetate past cleaving off acetyl-CoA from the HMG-CoA intermediate. Spontaneous decarboxylation of acetoacetate generates the dead-end product acetone.

Figure 6.24. Acetate must exist activated earlier it can be utilized

Figure 6.25. Ketogenesis frees up coenzyme A From acetyI-CoA

Acetoacetate can also exist reduced to beta-hydroxybutyrate past NADH-dependent three-hydroxybutyrate dehydrogenase (EC1.ane.1.30). This enzyme is allosterically activated past phosphatidyl choline. The reaction is fully reversible. Net flux depends on substrate concentrations. Acetoacetate and beta-hydroxybutyrate (but not acetone) can go a significant energy fuel for brain after several days of adaptation to starvation conditions.

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Inborn Errors of Metabolism

Richard J. Martin MBBS, FRACP , in Fanaroff and Martin's Neonatal-Perinatal Medicine , 2020

Defects of Ketogenesis.

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (also known as iii-hydroxy-three-methylglutaric aciduria) is an autosomal recessive disorder of ketogenesis. 99 This deficiency affects ketone body formation from fat acid β-oxidation and from leucine catabolism. This disorder tin can, therefore, be classified as an amino acid disorder and a fatty acid β-oxidation defect, which is characterized past an abnormal urine organic acrid pattern. The defect interferes with the major pathways of ketone body formation and consequently is a cause of severe nonketotic hypoglycemia and acidosis in the newborn infant. Patients by and large have airsickness, hypotonia, or lethargy at presentation, but others present with seizures caused past the profound hypoglycemia associated with this disorder. This disorder is treated with frequent feedings of a combined depression-fat/depression-poly peptide/leucine-restricted diet and carnitine supplementation. Other treatment modalities described above for the organic acidurias may also be helpful.

Ketone Body Metabolism in the Neonate

Baris Ercal , Peter A. Crawford , in Fetal and Neonatal Physiology (Fifth Edition), 2017

L-(+)-Β-Hydroxybutyrate

Although hepatic ketogenesis produces only d-(–)-βOHB, the physiologic substrate used for oxidation, L-(+)-βOHB is measurable in ketolytic tissues merely not in the circulation. L-(+)-βOHB is generated from the hydrolysis of the β-oxidation intermediate L-(+)-βOHB-CoA simply is non a BDH1 substrate. 153-156 SLC16A transporters in rat myocytes do not demonstrate stereoselectivity for βOHB. 157 In brains of suckling rats, Fifty-(+)-βOHB can exist used for synthesis of fatty acids and sterols. 91,92 These observations may be important when racemic dl-βOHB is administered to humans or used for experiments.

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Metabolism in Surgical Patients

Courtney M. Townsend JR., MD , in Sabiston Textbook of Surgery , 2022

Ketogenesis

The termketone body more often than not refers to iii substances: β-hydroxybutyrate, acetoacetate, and acetone. 2 , 3 , 6 When carbohydrate availability is extremely low, such as during fasting or starvation when gluconeogenesis and glycogenolysis have been exhausted, the trunk will switch to a reliance on ketone bodies as fuel substrates. 2 , three , 6 For example, while the encephalon normally uses glucose for energy, past the 4th day of fasting, the brain obtains about seventy% of its energy from ketone bodies. ii , iii , 6 Acetyl-CoA generated via fatty acid degradation would usually enter the TCA bike; however, because oxaloacetate is depleted by ongoing gluconeogenesis during starvation, acetyl-CoA is instead used to form ketone bodies. 2 , 3 , 6 The ketone bodies, in plough, can exist broken down into pyruvate for utilize equally fuel by the brain, centre, and muscles. 2 , 3 , 6

Ketoacidosis

Mitchell L. Halperin MD, FRCPC , ... Marc B. Goldstein Dr., FRCPC , in Fluid, Electrolyte and Acid-Base of operations Physiology (4th Edition), 2010

Metabolic procedure

The start step in ketogenesis is the hydrolysis of triglycerides to yield fat acids. In the liver, control of ketogenesis is largely due to the blocking of other pathways in the metabolism of the carbon product of fat acid oxidation, acetyl-CoA (oxidation and fat synthesis). The ketoacids formed become the main fuel for the brain.

In the process of ketogenesis, fatty acids are converted to ketoacids, if ane were to look at only the "carbon biochemistry." From an overall perspective, there are 2 other substrates to consider: NAD+ and ADP (+ inorganic phosphate).

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Ketone Bodies

Oliver E. Owen , Richard Due west. Hanson , in Encyclopedia of Endocrine Diseases, 2004

Biochemistry Of Ketogenesis And Ketolysis

Later CoA was discovered and accurate methods for measuring β-OHB, AcAc, and acetone became bachelor, knowledge regarding ketogenesis speedily grew. It was soon recognized that ketone bodies were non just intermediates in the oxidation of fatty acids but rather end-products that crave their ain enzymatic machinery for synthesis. The germination of ketone bodies occurs primarily in the liver via the post-obit enzymatic reactions, all of which are nowadays in the mitochondrial matrix, except for the spontaneous decarboxylation of AcAc to acetone, which occurs in the claret.

The reactions of ketone body synthesis are as follows:

1.

2 Acetyl CoA → Acetoacetyl CoA + coASH

ii.

Acetoacetyl CoA + Acetyl CoA → β-Hydroxy-β-methyglutaryl CoA

3.

β-Hydroxy-β-methyglutaryl CoA → Acetoacetate + acetyl CoA

4.

Acetoacetate + NADH ↔ β-Hydroxybutyrate + NAD

five.

Acetoacetate → Acetone + CO2

The enzymes of ketone trunk synthesis are as follows: (1) Acetoacetyl CoA thiolase; (2) β-hydroxy-β-methyglutaryl CoA synthase; (three) β-hydroxy-β-methyglutaryl CoA lyase; (four) β-hydroxybutyrate dehydrogenase; and (5) Spontaneous decarboxylation.

The major source of ketone bodies is the oxidation of fatty acids in the liver. The kidney can synthesize, oxidize, and excrete ketone bodies. The pathway of ketogenesis in the renal cortex is different from that in the liver. A pocket-sized quantity of AcAc tin be synthesized from ketogenic amino acids during starvation. In addition, infinitesimal quantities of β-OHB can be synthesized by the central nervous organisation. The enzymes involved in the hepatic synthesis of ketone bodies are listed above. Although small quantities of acetoacetyl CoA may ascend from the terminal four carbons of long-concatenation fat acids during β-oxidation, the bulk of acetoacetyl CoA is formed from a caput-to-tail condensation of two molecules of acetyl CoA via reversal of the acetoacetyl CoA thiolase reaction. Another acetyl CoA molecule combines with AcAc-CoA to grade β-hydroxybutyrate-β-methylglutaryl CoA (HMG-CoA) via the action of HMG-CoA synthetase. Generation of HMG-CoA simultaneously generates a proton; for each molecule of HMG-CoA committed to AcAc formation, one proton is released into the body fluids. HMG-CoA synthetase is virtually exclusively localized to the liver. In the next step in ketogenesis, HMG-CoA lyase cleaves HMG-CoA to class gratuitous AcAc and acetyl CoA. AcAc, the parent ketone body, tin can be converted to β-OHB by mitochondrial β-hydroxybutyrate dehydrogenase.

Ketone bodies tin be used for free energy by most tissues. The exceptions are the liver as well as tissues that have no mitochondria, such every bit carmine claret cells and the lens of the eye. The liver produces ketone bodies but has an undetectable or low activity of succinyl CoA:acetoacetyl CoA transferase, the major enzyme involved in ketone body degradation. Thus, hepatic activation of AcAc for hepatic oxidation is minimal and ketone bodies are released into the blood. The enzymes involved in the degradation of the major ketone bodies, AcAc and β-OHB, in this sequence are listed below. The catabolism of acetone is more complex and is discussed below.

The reactions of ketone torso degradation are equally follows:

1.

β-Hydroxybutyrate + NAD ↔ Acetoacetate + NADH + H+

2.

Acetoacetate + succinyl CoA ↔ Acetoacetyl CoA + succinate

three.

Acetoacetyl CoA + CoASH ↔ 2 Acetyl CoA

The enzymes of ketone body degradation are as follows: (one) β-hydroxybutyrate dehydrogenase; (2) Succinyl CoA:acetoacetyl CoA transferase; and (3) Acetoacetyl CoA thiolase.

At that place are several differences in the metabolism of ketone bodies in the kidney and in the liver. There is negligible activity of HMG-CoA synthase in the kidney cortex. In addition, the kidney possesses considerable activeness of succinyl CoA:acetoacetyl CoA transferase, an enzyme that is absent in the liver. Both organs take acetoacetyl CoA thiolase. The liver can synthesize and release both AcAc and β-OHB into the blood (simply information technology cannot metabolize the ketone bodies farther), whereas the kidney synthesizes these compounds past reversing the thiolase reaction. However, cyberspace renal ketogenesis is depression compared to the charge per unit of ketone body synthesis in the liver.

One important factor in the oxidation of ketone bodies is the concentrations of AcAc and β-OHB in biological fluids. AcAc enters the cell from the extracellular fluid or tin be produced in the mitochondria from β-OHB past β-hydroxybutyrate dehydrogenase. Since this reaction reduces NAD to NADH, β-OHB has a greater caloric value than AcAc (4.5 kcal/k versus four.0 kcal/thou). The overall rate of conversion of β-OHB to AcAc is also determined by the oxidation–reduction state (NAD/NADH) of cells in the tissue using the ketone bodies. This ratio can be influenced by a number of factors, including the rate of energy utilization by the tissue and the extent of fat acid oxidation that generates both NADH and FADHii directly in the mitochondrial matrix. Mitochondrial activation of AcAc in the brain, skeletal muscle, and heart is catalyzed by succinyl CoA transferase, which uses the CoA from succinyl CoA. Acetoacetyl CoA is then cleaved by acetoacetyl CoA thiolase into two molecules of acetyl CoA and the acetyl CoA then enters the tricarboxylic acid (TCA) cycle for oxidation to CO2.

Succinyl CoA:acetoacetyl CoA transferase is detected in all tissues with mitochondria except the liver. The synthesis of acetoacetyl CoA via this enzyme occurs at an energy toll since the succinyl CoA that is the CoA donor in this reaction would ordinarily be converted to succinate via succinyl CoA synthase in the TCA bicycle, generating a molecule of GTP. The highest activity of succinyl CoA:acetoacetyl CoA transferase is in the myocardium > brain > kidney > other tissues. Acetoacetyl CoA thiolase is nowadays in both the mitochondria and the cytosol. In the mitochondria, it promotes the cleavage of AcAc-CoA into acetyl CoA for oxidation in the TCA wheel.

A significant proportion of the AcAc that is produced is converted to acetone by nonenzymatic decarboxylation. Furthermore, an acid environment promotes AcAc decomposition to acetone. For each molecule of AcAc decomposed to class acetone, one H+ is consumed in the formation of CO2. Acetone product is direct related to the concentration of AcAc that is present in the blood; during diabetic ketoacidosis, approximately fifty% of the AcAc produced is converted into acetone. Acetone has a relatively slow rate of turnover, in role due to the large puddle of acetone in the body during protracted hyperketonemia. Acetone is converted irreversibly to acetol and and so to propyleneglycol (1,2-propanediol). Propanediol is converted to pyruvate, a gluconeogenic precursor. Thus, acetone metabolism violates the general rule that fatty acids (other than propionate) cannot support glucose synthesis in mammals.

The potential importance of acetone metabolism during starvation and diabetes has largely been ignored. Several reports demonstrated that acetone was present in blood, jiff, and urine. Although information technology has been long held that the blood of patients suffering from diabetic ketoacidosis contained little free acetone, Sulway and Malins reported strikingly elevated concentrations of free acetone in the bloodstream of 27 diabetic patients admitted to the hospital in diabetic ketoacidosis. These observations take been neglected by most investigators studying ketone body metabolism. However, there is a general consensus that the overall importance of acetone equally a precursor (or fuel) is pocket-sized compared to AcAc and β-OHB.

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Book ane

Toshia R. Myers BS, MA, MPhil, PhD , Alan Goldhamer DC , in Textbook of Natural Medicine (Fifth Edition), 2020

Metabolic Stage 5 (Until Nutrient Depletion Begins)

Phase V begins when rates of ketogenesis exceed gluconeogenesis and continues until starvation begins. 11 The length of this phase depends on an individual's body mass index, fatty and muscle percentages, physical activity levels, and state of health. Studies on respiratory quotient and urinary nitrogen take demonstrated that adipose TAG stores meet the bulk of whole-trunk energy requirements during prolonged fasting. 35,49,51,56,85 Meeting free energy requirements through fat metabolism decreases dependency on gluconeogenesis, thus sparing protein. 86,96 The brain begins utilizing ketone bodies, primarily βOHB, afterwards approximately four days. This adaption is essential because brain glycogen content is very low (0.1%). The brain (40 g/day) and other tissues (twoscore 1000/day) still take an obligatory demand for approximately fourscore 1000/twenty-four hours of glucose, which is met through gluconeogenesis. 8,97 Starvation begins when essential proteins are catabolized to meet energy requirements. 8 Based on average food reserves, a 70-kg human tin can fast for ii to three months before inbound starvation (Tables 37.2 and 37.3). viii,35,49,51,97,185-189

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Volume 1

Edward S. Ogata , in Fetal and Neonatal Physiology (4th Edition), 2011

Consequences of Prolonged Maternal Fasting

If maternal fasting is prolonged, maternal ketogenesis as a result of these endocrine changes volition be prolonged and exaggerated. Ketone bodies readily cross the placenta, and the fetal brain can employ ketones as early as 10 to 12 weeks gestation. 23 Although the capability to use an alternative fuel to glucose may be benign for the fetus, limited data suggest that the children of mothers who had ketosis during pregnancy are at take a chance for cognitive and psychomotor delays during childhood. The mechanisms responsible for this potential clan between ketone torso oxidation and impaired encephalon part are unclear. 25

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Ketosis

D.H. Williamson , in Encyclopedia of Human Diet (Tertiary Edition), 2013

Extrahepatic Regulation

A key factor in the regulation of ketogenesis is the availability of nonesterified long-chain fatty acids to the liver, which in turn is controlled by their release from adipose tissue. The enzyme responsible for the initiation of the hydrolysis of stored triacylglycerols to fatty acids is hormone-sensitive lipase. As its name implies, this enzyme is exquisitely sensitive to hormones: adrenaline (in the plasma) and noradrenaline (released from sympathetic nerve endings) are activators, whereas insulin inhibits the activity. In modest mammals glucagon is also an activator of the enzyme, merely this does not seem to be the case in the homo.

Insulin has an boosted consequence on the internet release of long-chain fat acids from adipose tissue in that it stimulates their re-esterification to triacylglycerols. Thus afterward a high-saccharide meal, when insulin secretion and its concentration in the plasma is high, the release of fat acids from adipose tissue is suppressed and their concentration in the plasma is low (Figure 2). In contrast, during stress, when adrenaline and noradrenaline are elevated, the release of fat acids is increased and their plasma concentration is loftier.

Figure 2. Intertissue fluxes of substrates in the fed state. Thickness of line denotes rate of flux.

In experimental animals increased plasma ketone body concentrations (hyperketonemia) can inhibit adipose tissue lipolysis (a) indirectly past increasing the secretion of insulin or (b) by a direct event on the tissue (Effigy 3). This can be viewed as a feedback mechanism for decision-making the rate of ketogenesis via fat acid supply to the liver, but whether this is important in the human being is non known. In dissimilarity, the supply of short- and medium-concatenation fat acids to the liver is mainly dependent on the dietary intake and on the proportion that escapes further metabolism in the intestinal tract; there is no known involvement of hormones in the process.

Figure 3. Part of ketone bodies every bit feedback regulators.

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