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While searching for literature on ketone bodies, I can only seem to find how they are synthesized, but not how they are broken down. I'm looking for the series of events with enzyme names and intermediates. Does anyone have this?
First, there are three ketone bodies: Acetone (top), acetoacetic acid (middle), and beta-hydroxybutyric acid (bottom), see the illustration from the Wikipedia:
The second and the third are taken up by heart and brain cells and then converted into Acetyl-CoA which is fed into the citric acid cycle where it is further metabolized. Acetone is mostly excreted. See here for some more information.
Aceto acetic acid is either converted into acetone and removed from the body or enzymatically converted into beta-hydroxybutyric acid by the beta-hydroxybutyrate dehydrogenase. The third possibility is that it is converted into Acetyl-CoA. See the figure for the scheme:
For a more detailed explanation of this process (both, the generation and the metabolization of the ketone bodies) see here.
A Ketogenic Diet Improves Mitochondrial Biogenesis and Bioenergetics via the PGC1α-SIRT3-UCP2 Axis
A ketogenic diet (KD high-fat, low-carbohydrate) can benefit refractory epilepsy, but underlying mechanisms are unknown. We used mice inducibly expressing a mutated form of the mitochondrial DNA repair enzyme UNG1 (mutUNG1) to cause progressive mitochondrial dysfunction selectively in forebrain neurons. We examined the levels of mRNAs and proteins crucial for mitochondrial biogenesis and dynamics. We show that hippocampal pyramidal neurons in mutUNG1 mice, as well as cultured rat hippocampal neurons and human fibroblasts with H2O2 induced oxidative stress, improve markers of mitochondrial biogenesis, dynamics and function when fed on a KD, and when exposed to the ketone body β-hydroxybutyrate, respectively, by upregulating PGC1α, SIRT3 and UCP2, and (in cultured cells) increasing the oxygen consumption rate (OCR) and the NAD + /NADH ratio. The mitochondrial level of UCP2 was significantly higher in the perikarya and axon terminals of hippocampus CA1 pyramidal neurons in KD treated mutUNG1 mice compared with mutUNG1 mice fed a standard diet. The β-hydroxybutyrate receptor GPR109a (HCAR2), but not the structurally closely related lactate receptor GPR81 (HCAR1), was upregulated in mutUNG1 mice on a KD, suggesting a selective influence of KD on ketone body receptor mechanisms. We conclude that progressive mitochondrial dysfunction in mutUNG1 expressing mice causes oxidative stress, and that exposure of animals to KD, or of cells to ketone body in vitro, elicits compensatory mechanisms acting to augment mitochondrial mass and bioenergetics via the PGC1α-SIRT3-UCP2 axis (The compensatory processes are overwhelmed in the mutUNG1 mice by all the newly formed mitochondria being dysfunctional).
Keywords: Bioenergetics Biogenesis Ketogenic diet MutUNG1.
Study Notes on Ketone Bodies
The below mentioned article provides a study note on the ketone bodies. After reading this article you will learn about: 1. Synthesis and Utilization of Ketone Bodies 2. Role of Ketone Bodies as an Aid to Diagnosis 3. Biochemical Changes in Ketosis and 4. Clinical Conditions of Ketosis.
There are three ketone bodies namely:
(2) Beta hydroxy butyric acid and
Ketone bodies are also known as ‘acetone bodies’. Formation of ketone bodies is known as ketogenesis. The ketone bodies are synthesized in the liver even under normal conditions.
Synthesis and Utilization of Ketone Bodies:
The ketone bodies are synthesized in the liver by the following reaction mechanism:
These ketone bodies cannot be utilized by the liver because the enzymes needed to activate them are absent or low in activity and hence these ketone bodies are supplied to the peripheral tissues for oxidation.
In the peripheral tissues the ketone bodies are utilized in the following manner:
Only acetoacetic acid and beta hydroxybutyric acid are easily oxidized by the extra hepatic tissue. Oxidation of acetone is difficult hence it is excreted in urine in large amounts than other ketone bodies, Acetone is also eliminated through the lungs hence starvation and diabetic patients show an alcoholic smell in their breath.
Role of Ketone Bodies as an Aid to Diagnosis:
There are three ketone bodies viz.:
(2) Beta hydroxy butyric acid
Ketone bodies are also known as Acetone bodies. Formation of ketone bodies is known as ketogenesis. The ketone bodies are synthesized in the liver even under normal conditions. The ketone bodies are produced from Acetyl CoA which comes from three sources.
Normal levels of ketone bodies in human beings:
The normal level of ketone bodies in the blood of human beings is less than 1 mg/dl and is excreted in the urine to less than 1 gm./day.
Methods of estimation of Ketone Bodies:
The presence or absence of ketone bodies in the urine is detected by Rothera’s test. Rothera’s test is also carried for the semi-quantitative estimation of ketone bodies in the blood, wherein the results obtained are—
(- ve) — Ketone bodies are less than 1 mg/100 ml of the blood
(+ ve) — Ketone bodies are little more than 1 mg/100 ml of the blood
(+ + ve) — Ketone bodies are about 1.5 mg/100 ml of the blood
(+ + + ve) — Ketone bodies are more than 2 mg/100 ml of the blood
There are two methods for the quantitative estimation of ketone bodies in blood:
The ketone bodies synthesized by the liver will continuously be utilized by the peripheral tissues. The peripheral tissues have a limited capacity to utilize the ketone bodies. If the production of ketone bodies by the liver exceeds the capacity of the peripheral tissues to utilize them, as in diabetics and starvation, then this results in accumulation of ketone bodies in blood a condition known as ketonemia and consequently there will be an increased excretion of ketone bodies in urine known as ketonuria. Both ketonemia and ketonuria together are known as ketosis.
Ketosis or keto acidosis is a condition in which there is an increased accumulation of ketone bodies in the blood (ketonemia) and consequently increased excretion in urine (ketonuria).
Biochemical Changes in Ketosis:
1. Acetoacetic acid and Beta hydroxyl butyric acid are strong acids their accumulation causes ketoacidosis, thereby lowering the pH of blood.
2. Buffering capacity is disrupted because bicarbonate of the blood decreases.
The low pH caused by ketosis leads to disturbance in the normal buffering mechanism of the blood. This leads to emergence of yet another buffering system in the blood i.e., the muscle proteins are released and hydrolyzed to amino acids which are oxidized releasing ammonia (NH3). NH3 takes up H + ions to form NH4 and thus compensates the acidity of blood. Ammonium ion is more destructive thereby causing more harm to the individual.
3. Along with ketone bodies large amounts of H2O and Na + ions are lost leading to electrolyte imbalance and dehydration.
Depression, thirst, fatigue and coma.
Clinical Conditions of Ketosis:
Clinical Conditions in Which Ketosis Occurs:
Includes both post fasting period i.e. 12-24 hours after meal or continuous starvation for days together. During this condition there may be lack of glucose leading to non-entry of glucose into adipose tissue resulting in lowered glycolysis and low intermediates of glycolytic pathway. Low concentration of glyceraldehyde-3-phosphate, an intermediate of glycolysis cannot be converted to glycerol phosphate and therefore there will be no re-esterification of fatty acids resulting in the release of fatty acids from adipose tissue into the blood.
As the period of starvation increases, the glucose concentration in the blood decreases leading to increased release of fatty acids producing more amounts of ketone bodies much more than the peripheral tissues can use them, causing ketosis. The ketone bodies are utilized by all the extra-hepatic tissues except brain in the initial stages. After three weeks of starvation, brain also shifts to the utilization of ketone bodies which leads to the destruction of brain cells due to ketosis.
(2) Diabetes mellitus:
Though glucose is present in large quantities in the blood, it cannot be utilized by the cells, results in the release of fatty acids and overproduction of ketone bodies causing ketoacidosis.
During the third trimester of pregnancy, the demand for glucose is doubled and hence there will be overproduction of ketone bodies leading to ketoacidosis.
During lactation more energy is required because glucose is utilized for:
(ii) Formation of milk fat and
(iii) Synthesis of milk protein casein.
This leads to depletion of glucose to adipose tissue resulting in more release of fatty acids producing more ketone bodies leading to ketosis. Ketosis is generally accompanied with low calcium levels which are referred to as milk fever. This is developed within hours in lactating mothers having twins or more babies which is characterized by sudden fall in blood pH and decrease in milk production.
(5) Febrile diseases:
In fever causing disease there is a demand for glucose for the formation of antibodies thereby depleting glucose to adipose tissue leading to ketosis.
(6) Heavy exercise:
Heavy physical exercise suddenly raises the level of ketone bodies and if the exercise is continued without intake of glucose then it may result in ketosis.
Starvation ketosis can be controlled by injecting anti-ketogenic substances like glucose and glucose producers like glycerol and glucogenic amino acids like glycine, glutamic acid, alanine, serine etc..
Ketones serve as an alternative energy source for the human body, specifically our mitochondria (the ‘powerhouse’ of cells) when carbohydrate intake is limited. They are a byproduct created when the body breaks down fat.
In simple terms, when you are eating a high-fat, low-carb diet, your body will begin to break down fat for energy instead of carbohydrates.
While you might argue that glucose (sugar) is the primary source of energy in humans, it is not essential for our survival.
Ketones, on the contrary, are byproducts of fat metabolism in humans when carbohydrates are restricted and are thus necessary substrates for us to live.
Note that BHB is not technically a ketone since it contains a reactive hydroxyl group where double-bonded oxygen would usually be.
Nevertheless, BHB still functions like a ketone in humans and can convert to energy (via acetyl-CoA), just like acetoacetate and acetone can be. However, the conversion of acetone to acetyl-CoA is rather inefficient.
What Are Ketones Exactly?
A google search for ketones will yield some results that refer to ketone bodies. In many cases, ketones and ketone bodies are used interchangeably, but they are not exactly the same thing.
Technically, ketones are organic compounds that contain a carbonyl group (a carbon atom double bonded to an oxygen atom) that is single bonded to two hydrocarbon groups made by oxidizing secondary alcohols. Did that organic chemistry go over your head?
Let’s look at an example of a ketone to help you understand it more clearly:
This is acetone — the simplest ketone. During the first couple weeks on the ketogenic diet, the body may make some of it and release it in the breath. This is why you may have bad breath during your first couple weeks on the ketogenic diet.
When you look at the picture of acetone, you will see a carbonyl group bonded to two hydrocarbon groups. The carbonyl group is the big “C” or carbon atom that is double bonded (marked by the double straight lines) to a big “O” or oxygen. That carbon atom is also single bonded (marked by single lines) to two hydrocarbon groups.
A hydrocarbon group is any compound consisting entirely of hydrogen and carbon. In our acetone molecule, you will find two hydrocarbon groups that are each called a methyl group. Each methyl group contains one carbon atom single bonded to three hydrogen molecules.
Is the organic chemistry still too complicated? Well, the good news is that it isn’t absolutely necessary to understand. All you really have to know is that acetone is simultaneously a ketone and a ketone body, while diacetyl — another naturally-occurring ketone that was a popular artificial butter-flavoring for popcorn — is just a ketone. You may also want to know why this is the case.
Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade
Limited experimental evidence bridges nutrition and cancer immunosurveillance. Here, we show that ketogenic diet (KD) - or its principal ketone body, 3-hydroxybutyrate (3HB), most specifically in intermittent scheduling - induced T cell-dependent tumor growth retardation of aggressive tumor models. In conditions in which anti-PD-1 alone or in combination with anti-CTLA-4 failed to reduce tumor growth in mice receiving a standard diet, KD, or oral supplementation of 3HB reestablished therapeutic responses. Supplementation of KD with sucrose (which breaks ketogenesis, abolishing 3HB production) or with a pharmacological antagonist of the 3HB receptor GPR109A abolished the antitumor effects. Mechanistically, 3HB prevented the immune checkpoint blockade-linked upregulation of PD-L1 on myeloid cells, while favoring the expansion of CXCR3+ T cells. KD induced compositional changes of the gut microbiota, with distinct species such as Eisenbergiella massiliensis commonly emerging in mice and humans subjected to carbohydrate-low diet interventions and highly correlating with serum concentrations of 3HB. Altogether, these results demonstrate that KD induces a 3HB-mediated antineoplastic effect that relies on T cell-mediated cancer immunosurveillance.
Keywords: Cancer Immunotherapy Metabolism Mouse models Oncology.
Conflict of interest statement
Conflict of interest: LZ, RD, and GK are founders of EverImmune.
Figure 1. Ketogenic diet decreases melanoma and…
Figure 1. Ketogenic diet decreases melanoma and renal cell tumor growth.
Figure 2. Ketone bodies accumulate in tissues…
Figure 2. Ketone bodies accumulate in tissues of ketogenic diet fed mice.
Figure 3. Ketone body 3-hydroxybutyrate (3HB) is…
Figure 3. Ketone body 3-hydroxybutyrate (3HB) is necessary and sufficient to account for the anticancer…
Figure 4. Ketogenic diet shifts the microbiota…
Figure 4. Ketogenic diet shifts the microbiota composition.
( A ) PCoA representing the differences…
Figure 5. Correlations between microbial species and…
Figure 5. Correlations between microbial species and ketone bodies in mice and humans.
Figure 6. T cell–dependent effects of ketogenic…
Figure 6. T cell–dependent effects of ketogenic diet and synergy with immune checkpoint blockade.
Figure 7. Intermittent 3HB scheduling affects systemic…
Figure 7. Intermittent 3HB scheduling affects systemic expression of T cell inhibitory receptor and their…
Figure 8. Efficacy of intermittent 3HB in…
Figure 8. Efficacy of intermittent 3HB in circumventing primary resistance to PD-1 blockade in an…
Ketones can also be present when your blood sugar is normal or low. These are sometimes referred to as “starvation ketones” or “nutritional ketones.” During an illness or extreme diet change, if you have a significant decrease in carb intake, this can lead to the body using fat for energy because there are not enough carbs present to burn. Your blood sugar could remain normal or even be low in this case but your body could still be producing ketones.
It is recommended that you drink 8 ounces of water or carb/caffeine free beverage every 30-60 minutes to help flush out the ketones. Again, ketones are a sign that your body needs more insulin. Some people might already have an insulin dosing plan in place related to ketones. It’s typically a percentage of your daily long-acting dose or percentage of your total daily basal volume (for pump users) based on whether ketones are small, moderate or large. It is always best to call your endocrinologist to verify what they recommend when ketones are present.
This piece is part of Beyond Type 1’s resources on DKA + managing ketones – find the complete collection of resources here.
The Role of Carbohydrate Response Element–Binding Protein in the Development of Liver Diseases
5.2 Ketone Bodies
Ketone bodies have an important role as an energy source during starvation. 100 In the liver, fatty acyl CoA is converted into ketone bodies (3-hydroxybutyrate [βOHB] and acetoacetate [AcAc]). 100 The ketone bodies are efficiently metabolized in peripheral tissues except in the brain. Hepatic ketogenesis is suppressed and upregulated by insulin and glucagon, respectively. The ketone bodies and AMP suppress ChREBP transactivity and de novo lipogenesis in the liver. 16–19
A ketogenic diet (high-fat and low-carbohydrate) have been used for drug-resistant epilepsy, diabetes, and obesity. 101–103 In addition, ketogenic diets have been shown to be beneficial in mouse models of several common human neurodegenerative diseases because βOHB has neuroprotective effects. 104,105 Recently, a ketogenic diet was introduced for obesity. Ketogenic diets can aid effective loss of body weight but may cause an increase in levels of LDL-C and FFAs. 106 Recently, a ketone ester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, was developed. 107–109 This ketone ester is hydrolyzed by gut esterases to yield absorbable βOHB and (R)-1,3-butanediol. 109 In the liver, (R)-1,3-butanediol is converted to AcAc and βOHB. (R)-3-hydroxybutyl (R)-3-hydroxybutyrate increased plasma levels of ketones but lowered levels of glucose, cholesterol, and TGs. 109 If (R)-3-hydroxybutyl (R)-3-hydroxybutyrate suppresses ChREBP through AMPK activation, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate might be a novel method to decrease de novo lipogenesis by suppression of ChREBP activity without increasing plasma levels of lipids.
Activation of Ketone Body Synthesis
From a biochemical perspective, ketone body synthesis will be reinforced whenever there is an increased presence of acetyl-CoA (the starting substance of ketone body synthesis), as occurs during long periods of fasting or starvation.
Diabetes mellitus also causes an accumulation of acetyl-CoA: lowered insulin production or higher insulin resistance leads to an increase in the degradation of fatty acids which, in turn, leads to more acetyl-CoA being produced. Acetyl-CoA can only enter the citric acid cycle if there is enough oxaloacetate available for the 1st reaction in that cycle however, in diabetes mellitus, the absorption of glucose from the blood into the cell is inhibited, leading to reduced activity of glycolysis and thus reduced production of pyruvate and oxaloacetate.
This means that patients with diabetes have increased amounts of acetyl-CoA and a simultaneous deficiency of oxaloacetate, resulting in an intensified synthesis of ketone bodies via the acetyl CoA and HMG-CoA pathways. As well, there is an attempt to increase the amount of oxaloacetate for the Krebs cycle via deaminated amino acids that are ketogenic, such as leucine. The synthesis of ketone bodies takes place mainly in the hepatocytic mitochondria.
Harnessing metabolic signals to treat geriatric syndromes of aging.
Understanding how cellular metabolism interacts with the genes and pathways that regulate aging has led to many of the potential interventions now being investigated to promote healthspan. Exercise, fasting, and dietary restriction all work to promote health by activating specific cellular signaling pathways. Many of these signaling pathways involve ordinary cellular metabolites like acetyl-CoA and NAD, which have “secret” lives regulating enzymes and genes. The Newman lab focuses on an emerging signaling metabolite, the ketone body beta-hydroxybutyrate, and the roles it may have in responding to stressors and regulating healthspan.
Ketone bodies are the energy currency that allows the body’s cells to utilize fats for fuel. They are made normally in the liver from fats whenever carbohydrates are scarce, as when fasting or exercising. Ketone bodies are to fats what glucose is to carbohydrates. But beta-hydroxybutyrate has signaling activities as well, including regulating gene expression, modulating inflammation, and controlling metabolism by inhibiting enzymes, binding to proteins, and activating receptors. We have found that long-term exposure to ketone bodies using a ketogenic diet can extend the healthy lifespan of normal mice and, in particular, protect the aging brain. We seek a mechanistic understanding of how ketone bodies might work in an aging mammal to promote health, particularly in age-related memory decline and Alzheimer’s disease. Our goal is to develop targeted therapies that might enhance the resilience of older adults to diseases like Alzheimer’s and stresses like hospitalization.
Why it matters
The translation of geroscience into clinical practice has great potential to improve the lives of older adults. We already know that the best way to treat the complex medical problems of older adults is through the systematic, individualized geriatric medicine approach of comprehensive assessments and multidomain interventions. Interventions developed from geroscience usually act on multiple aging-related cellular pathways, like how the signaling activities of ketone bodies affect gene expression, inflammation, and metabolism. These interventions may hold great promise for treating complex geriatric syndromes like frailty, multimorbidity, and delirium that affect the health and independence of millions of older adults.