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Relationship: 880

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

Decreased, PPARalpha transactivation of gene expression leads to Decreased, Ketogenesis (production of ketone bodies)

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 adjacent Moderate Moderate 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 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
Mus musculus Mus musculus High NCBI
Homo sapiens Homo sapiens High NCBI
Rattus rattus Rattus rattus High 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

PPARα is a transcriptional regulator for a variety of genes that facilitate systemic energy homeostasis (Kersten 2014, Evans et al 2004, Desvergne and Wahli 1999).  The KE, “decreased PPARα transactivation of gene expression” results in the KE, “decreased transcriptional expression for genes that catalyze ketogenesis” (Cahil 2006, Kersten et al. 2014, Sengupta et al. 2010, Desvergne and Wahli 1999) by inhibiting expression of the enzymes involved in ketogenesis.  Enzyme description (Kersten 2014, Sengupta et al. 2010) and metabolic flux examinations (Sengupta et al. 2010) additionally providing fairly robust characterization in support of the KER.  Ketogenesis is critical to supporting general systemic energy homeostasis in fasting events (Cahill 2006, Evans et al 2004, Sengupta et al 2010), thus KE4 becomes important after short term energy stores (glycogen) become limited (Muoio et al 2002).  Le May, et al (2000) have shown decreased ketogenesis  in livers of PPAR null mice linked to impaired mitochondrial hydroxymethylglutaryl-CoA synthase (Hmgcs) gene expression.

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

Inhibition of PPARα signaling has been demonstrated to inhibit transcriptional expression of genes that catalyze ketogenesis as well as ketone body production (Badman et al 2007, Potthoff 2009, Sengupta 2010) affecting circulating levels of ketone bodies for systemic use.  Kersten et al (1999) demonstrated that PPARα is induced in fasted mice mobilizing the oxidation of fatty acids for energy production. In that study, PPARα-null mice did not actively induce fatty acid oxidation or ketogenesis leaving the mice unable to meet energy demands during fasting and leading to hypoglycemia, hyperlipidemia, hypoketonemia and fatty liver.  Upstream metabolic events, such as the KEs “peroxisomal fatty acid beta oxidation” and “mitochondrial fatty acid beta oxidation” play a key role in producing substrates for ketogenesis.  Although the connection between the KE, “decreased PPARα transactivation of gene expression” -> the KE, “decreased ketogenesis” is well established given the literature cited above, the dependency on the KEs “peroxisomal fatty acid beta oxidation” and “mitochondrial fatty acid beta oxidation” for substrate availability can affect the KE, “decreased ketogenesis” in addition to the influence of the up-stream KE, “decreased PPARα transactivation of gene expression, therefore we scored the KER for the KE, “decreased PPARα transactivation of gene expression” -> the KE, “Ketogenesis (production of ketone bodies)” as “moderate”.

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 description 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

A critical data gap regarding this AOP is an absence of studies that have investigated the effects null mutants for ketogenesis on the physiology and individual performance during long term starvation relative to wild type individuals.

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

Ketogenesis is more prevalent in fasted state.

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

A period of fasting such that available glucose is consumed is usually a pre-requisite for increased ketogenesis.

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

Evidence provided for human in Cahill (2006), Owen et al (2005) and Williamson et al (1962).  Evidence for mouse provided in Kersten et al (1999).  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 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.

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

Kersten S.  2014. Integrated physiology and systems biology of PPARalpha. Molecular Metabolism 2014, 3(4):354-371.

Lazarow, P.B., 1978. Rat liver peroxisomes catalyze the beta oxidation of fatty acids. J. Biol. Chem. 253, 1522-1528.

Le May et al., 2000. Reduced hepatic fatty acid oxidation in fasting PPARK null mice is due to impaired mitochondrial hydroxymethylglutaryl-CoA synthase gene expression. FEBS Lett. 475: 163-166.

Mannaerts GP, Van Veldhoven PP 1993 Metabolic role of mammalian peroxisomes. In: Gibson G, Lake B (eds) Peroxisomes: Biology and Importance in Toxicology and Medicine. Taylor & Francis, London, pp 19–62.

Nelson DL, Cox MM 2000A.  The Citric Acid Cycle. Lehninger Principles of Biochemistry. 3rd Edition.  Worth Publishers.  New York, NY. p567-592.

Nelson DL, Cox MM 2000B.  Carbohydrate Biosynthesis. Lehninger Principles of Biochemistry. 3rd Edition.  Worth Publishers.  New York, NY. p722-764.

Nelson DL, Cox MM 2000C.  Lipid Biosynthesis. Lehninger Principles of Biochemistry. 3rd Edition.  Worth Publishers.  New York, NY. p770-814.

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.

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.