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Event: 862

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Not Increased, Circulating Ketone Bodies

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Not Increased, Circulating Ketone Bodies
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Tissue

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
blood

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
abnormal lipid homeostasis abnormal
ketone body abnormal

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
PPARα antagonism leading to body-weight loss KeyEvent Kurt A. Gust (send email) Open for citation & comment WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Not Otherwise Specified Not Specified
Adults High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Male High
Female High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

A fundamental process in biological systems is the production of metabolic fuel for use in meeting the energy demands of cells and, in multi-cellular organisms, supporting overall systemic energy needs.  Physiological studies of the progression of human starvation have identified that the preferred metabolic fuel is glucose in the fed state and progressing through two days of fasting, afterward ketone bodies become increasingly important for meeting energy demands (Cahill 2006, Owen et al 2005).  Substrates derived from carbohydrates, fats and protein can contribute to gluconeogenesis (Cahill 2006, Gerich et al 2001) whereas substrates derived from fatty acids are the primary contributors to ketogenesis (Desvergne and Wahli 1999).  Mobilization of fatty acids as a metabolic fuel source increase dramatically during fasting to support both gluconeogenesis and ketogenesis (Evans et al 2004).   Cahill (2006) and colleagues have demonstrated the importance of ketone body production, especially β-hydroxybutyrate, for maintaining energy homeostasis during starvation.  β-hydroxybutyrate serves as an alternative substrate to glucose for providing energy to the brain in the starvation state, providing ATP at higher efficiency relative to the glucose substrate (Cahill 2006).  Interference with ketogenesis, for example by PPARα inhibition, has been demonstrated to inhibit β-hydroxybutyrate production (measured in serum) during fasting events in mice (Badman et al 2007, Potthoff 2009, Sengupta et al 2010) and cause hypoketonemia (Muoio et al 2002).  The Badman et al (2007) study indicated that metabolism of fatty acid substrates (measured as liver triglycerides) that would otherwise contribute to β-hydroxybutyrate production was inhibited under PPARα knockout.   Increased concentrations of circulating ketone bodies is indicative of potential metabolic fuel deficits in fasting animals (Cahill 2006), and a lack of increase in circulating ketone bodies during fasting, especially in conjunction with elevated blood triglycerides, indicates impaired ketogenesis and potentially impaired bioenergetic potential. Although the potential therapeutic implications of increased ketone body metabolism via ketogenic diets for various disease states has been discussed (Veech 2004), no studies were found demonstrating effects on whole organism responses to impaired ketogenesis over long-term starvation events.  A potential implication of decreased ketone body production is stress on cardiac function given that energy-stressed heart tissue shifts reliance away from fatty acids toward ketone bodies (β-hydroxybutyrate) to fuel production of the ATP needed to maintain the heart’s mechanical function (Aubert et al 2016).  Related to this observation, PPARα-knockout mice reached exhaustion sooner than wild types in an exercise challenge which corresponded with significantly decreased β-hydroxybutyrate in serum indicating hypoketonemia in PPARα-knockout mice versus wild types (Muoio et al 2002).  Overall, diminished PPARα function, especially in combination with fasting /diminished nutrition and/or excessive exercise may contribute to impaired maintenance on systemic energy budget.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

The quantification of β-hydroxybutyrate described in Cahill 2006 was measured in a cell-free system catalyzed by D(-)-p-hydroxybutyric dehydrogenase where all components of the reaction  [ D(-)-fl-hydroxybutyrate + diphosphopyridine nucleotide + = acetoacetate + reduced diphosphopyridine nucleotide + H+ ] were able to be quantitatively determined (Williamson et al 1962).  Serum β-hydroxybutyrate was measured using Stanbio Laboratory small-scale enzymatic assays in Badman et al (2007) and by Wako Chemicals D-3-hydroxybutyric acid kit in Potthoff et al (2009).  SMART micro-FPLC (Amersham Biosciences) consisting of a Superose 6 PC 3.2/30 column (Amersham Biosciences) equilibrated in PBS buffer was conducted where triglyceride and cholesterol fractions were investigated by enzymatic assay (Wako Diagnostics) as described in Badman et al (2007).  Clinical observations of ketone bodies have been simplified by the development of urine test strips that can provide quantitative values for the ketone bodies aceto-acetate, acetone and 3-hydroxybutyrate using reflectometry (Penders et al 2005).  The transition from using fatty acids to ketone bodies to fuel ATP production in cardiac muscle was measured in isolated heart preparation using ex vivo NMR combined with targeted quantitative myocardial metabolomic profiling using mass spectrometry  (Aubert et al 2016).  In Muoio et al (2002), β-hydroxybutyrate was measured in blood serum where wild type and PPARα knockout mice were compared.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

Evidence for mouse was provided in (Badman et al 2007, Potthoff 2009).   Evidence for human was provided in (Cahill 2006, Owen et al 2005, Gerich et al 2001).  Comparative investigations of ketone body formation comparing human and mouse is not well established relative to fatty-acid oxidation comparisons.

References

List of the literature that was cited for this KE description. More help

Aubert, G., Martin, O.J., Horton, J.L., Lai, L., Vega, R.B., Leone, T.C., Koves, T., Gardell, S.J., Kruger, M., Hoppel, C.L., Lewandowski, E.D., Crawford, P.A., Muoio, D.M., Kelly, D.P., 2016. The Failing Heart Relies on Ketone Bodies as a Fuel. Circulation 133, 698-705.

Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E: Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell metabolism 2007, 5(6):426-437.

Cahill GF, Jr. Fuel metabolism in starvation. Annu Rev Nutr 2006, 26:1-22.

Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Reviews 20(5): 649-688.

Evans RM, Barish GD, Wang YX: PPARs and the complex journey to obesity. Nat Med 2004, 10(4):355-361.

Gerich JE, Meyer C, Woerle HJ, Stumvoll M: Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 2001, 24(2):382-391.

Muoio, D.M., MacLean, P.S., Lang, D.B., Li, S., Houmard, J.A., Way, J.M., Winegar, D.A., Corton, J.C., Dohm, G.L., Kraus, W.E., 2002. Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta. J. Biol. Chem. 277, 26089-26097.

Owen OE: Ketone bodies as a fuel for the brain during starvation. Biochem Mol Biol Educ 2005, 33(4):246-251.

Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, Mohammadi M, Finck BN, Mangelsdorf DJ, Kliewer SA et al: FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proceedings of the National Academy of Sciences 2009, 106(26):10853-10858.

Veech RL: The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fatty Acids 2004, 70(3):309-319.

Williamson DH, Mellanby J, Krebs HA: Enzymic determination of d(−)-β-hydroxybutyric acid and acetoacetic acid in blood. Biochem J 1962, 82(1):90-96.