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Relationship: 884

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Not Increased, Circulating Ketone Bodies leads to Increased, Catabolism of Muscle Protein

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Antagonist binding to PPARα leading to body-weight loss non-adjacent Moderate Low Agnes Aggy (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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens Moderate NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male Moderate
Female Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adults Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

A fundamental process in all biological systems is the production of metabolic fuel for use in meeting the energy demands of cells and the systemic energy needs of multi-cellular organisms.  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 (KE5, 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).  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.

After two to three days of fasting in humans, dietary glucose has been long-since expended and contribution to blood glucose from glycogen metabolism is reduced to zero (Cahill 2006).  At this point, about two fifths of fatty acid metabolism in the whole body is dedicated to hepatic ketogenesis, largely in support of the energy demands of the brain, however the brain is still significantly supported by glucose derived from gluconeogenesis (Cahill 2006).  PPARα knockout mice that were either fasted or exercised to exhaustion had diminished capacity for maintaining energetic substrates in serum (glucose and lactate) while showing diminished capacity for fatty acid oxidation (serum nonesterified fatty acids) and decreased ketogenesis resulting in hypoketonemia (decreased serum β-hydroxybutyrate) relative to wild types (Muoio et al 2002).  As fatty acid stores are depleted or become unusable (as in the PPARα knockout condition described above), gluconeogenesis from other substrates becomes increasingly important including muscle protein catabolism in situ for supporting muscle function as well as releasing glutamine (Marliss et al 1971) and alanine (Felig et al 1970A) which can be recycled to glucose by gluconeogenesis in the kidney (Goodman et al 1966, Kashiwaya et al 1994, Cahill 2006).  Renal gluconeogenesis from glutamine and alanine supports two fifths of new glucose production while the remaining three fifths is produced in liver from, (a) alanine derived from muscle and nonhepatic splanchnic bed, (b) recycled lactate and pyruvate from red blood cells and renal medulla, (c) glycerol from adipose lipolysis and (d) small amounts of β-hydroxybutyrate are recycled to glucose (Cahill 2006).  Blood concentrations of alanine exert control over hepatic glucose production and thus also represent a diagnostic of alanine contribution from muscle to support gluconeogenesis (Cahill 2006, Felig et al 1970B).  In prolonged starvation events, the catabolism of muscle protein (KE6) for gluconeogenesis in order to support systemic energy needs results in loss of muscle mass which contributes to loss of overall body weight.  Although it has not yet been investigated experimentally, it is plausible based on the results described above for Muoio et al (2002) that diminished PPARα signaling capacity could exacerbate muscle wasting in long-term fasting and/or malnutrition events.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

The scoring for the KER, where the KE, “no increase in circulating ketone bodies” -> the KE, increased, catabolism of muscle protein” reflected the observation that amino acid recycling to glucose via renal gluconeogenesis (Goodman et al. 1966, Kashiwaya et al. 1994) is a broadly separate process and under separate regulatory control from ketogenesis (Felig et al. 1970B, Sengupta et al. 2010).  However, under starvation conditions in conjunction with diminished circulating ketone bodies to serve as fuel for systemic metabolism, an increase in catabolism of muscle protein would be required to support renal gluconeogensis to sustain the systemic energy budget.  Therefore, although the KER, for the KE, “no increase in circulating ketone bodies” -> the KE, increased, catabolism of muscle protein” lacks a mechanistic connection, a strong correlative relationship exists between the KEs regarding energy homeostasis, hence the weight of evidence for the KER was scored as “moderate” however the quantitative understanding was scored as “weak”.

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Biological plausibility of this KER is strong given the supporting relationships cited in the literature described in the previous bullets above.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

See previous section.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Availability of alternative energy substrates may chance the dynamics of this KER.

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

Unknown.

Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

The timescale is dependent on availability of alternative energy reserves including glycogen and fatty acids.

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Ketogenesis diminishes after transition from a fasted state to a fed state

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The relationships described herein have been primarily established in human and rodent models.

References

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

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.

Felig P, Pozefsky T, Marliss E, Cahill GF, Jr.: Alanine: key role in gluconeogenesis. Science 1970A, 167(3920):1003-1004.

Felig P, Marliss E, Pozefsky T, Cahill GF, Jr.: Amino acid metabolism in the regulation of gluconeogenesis in man. Am J Clin Nutr 1970B, 23(7):986-992.

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

Goodman AD, Fuisz RE, Cahill GF: Renal gluconeogenesis in acidosis, alkalosis, and potassium deficiency: its possible role in regulation of renal ammonia production. J Clin Invest 1966, 45(4):612-619.

Kashiwaya Y, Sato K, Tsuchiya N, Thomas S, Fell DA, Veech RL, Passonneau JV: Control of glucose utilization in working perfused rat heart. J Biol Chem 1994, 269(41):25502-25514.

Marliss EB, Aoki TT, Pozefsky T, Most AS, Cahill GF: Muscle and splanchnic glutamine and glutamate metabolism in postabsorptive and starved man. J Clin Invest 1971, 50(4):814-817.

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.

Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM: mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 2010, 468(7327):1100-1104.

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.