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Relationship: 881

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, Peroxisomal Fatty Acid Beta Oxidation of Fatty Acids leads to Decreased, Mitochondrial Fatty Acid Beta Oxidation

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Decreased, Peroxisomal Fatty Acid Beta Oxidation of Fatty Acids

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Decreased, Mitochondrial Fatty Acid Beta Oxidation

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

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
Not Otherwise Specified	Not Specified

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

Peroxisomes participate in a variety of lipid metabolic pathways including the beta-oxidation of very long-straight chain (<20 C in length) or branched –chain acyl-CoAs (Lazarow 1978, Kersten 2014). The peroxisomal beta-oxidation pathway is not directly coupled to the electron transport chain and oxidative phosporylation, therefore the first oxidation reaction loses energy to heat (H2O2 production) while in the second step, energy is captured in the metabolically accessible form of high-energy electrons in NADH (Mannaerts and Van Veldhoven 1993, Desvergne and Wahli 1999). The peroxisomal beta-oxidation pathway provides fatty acid chain shortening where two carbons are removed in each round of oxidation in the form of acetyl-CoA (Desvergne and Wahli 1999). The shortened chain fatty acids (<20C) can then be transported to the mitochondria to undergo mitochondrial beta-oxidation for complete metabolism of the carbon substrate for cellular energy production (Desvergne and Wahli 1999). Mitochondrial beta-oxidation catabolizes short, medium and long chain fatty acids (<C20) into acetyl-CoA and ATP. The production of acetyl-CoA monomers is important as they serve as fundamental units for metabolic energy production (ATP) via the citric acid cycle followed by electron-transport chain mediated oxidative phosphorylation (Nelson and Cox, 2000A). Acetyl-CoA is also a fundamental units of energy storage via gluconeogenesis (Nelson and Cox, 2000B) and lipogenesis (Nelson and Cox, 2000C).

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 KE, “peroxisomal fatty acid beta oxidation of fatty acids” reactions shorten very long chain fatty acids from dietary sources releasing acetyl-CoA subunits (a primary metabolic fuel source) and shortened-chain fatty acids that can subsequently be catabolized in the KE, “mitochondrial fatty acid beta oxidation” (as reviewed in Kersten et al. 2014 and Desvergne and Wahli 1999). Although the KER for these KEs is firmly established, the KE, “mitochondrial fatty acid beta oxidation” is not dependent on the KE, “peroxisomal fatty acid beta oxidation of fatty acids” given that the latter occur using short, medium and long chain fatty acids from diet or when released from adipose tissue (Desvergne and Wahli 1999, Evans et al. 2004), hence the “Moderates” score for weight of evidence and quantitative understanding.

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.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Include consideration of temporal concordance here

As described in the previous sections, there is a fundamental linkage between KEs given that the KE, “peroxisomal fatty acid beta oxidation of fatty acids” produces raw materials that can be used in the KE, “mitochondrial fatty acid beta oxidation”. It is less clear how essential the latter is to a sustainable throughput of the former.

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

The degree to which the KE, “peroxisomal fatty acid beta oxidation of fatty acids” contributes to the KE, “mitochondrial fatty acid beta oxidation” under a broad range of nutrient levels and types is not well characterized.

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

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

As discussed in the previous sections, the degree to which the KE, “peroxisomal fatty acid beta oxidation of fatty acids” contributes to the KE, “mitochondrial fatty acid beta oxidation” is not well described, neither are modulators of the response-response relationship. We are not currently aware of any models available to extrapolate results among KEs.

Response-response Relationship

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

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

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

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 evidence provided is primarily derived from human and rodent models.

References

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

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

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

Lazarow PB: Rat liver peroxisomes catalyze the beta oxidation of fatty acids. J Biol Chem 1978, 253(5):1522-1528.

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.