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Relationship: 110

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

Synthesis, De Novo Fatty Acid (FA) leads to Accumulation, Triglyceride

Upstream event

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

Synthesis, De Novo Fatty Acid (FA)

Downstream event

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

Accumulation, Triglyceride

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
LXR activation leading to hepatic steatosis	adjacent	Not Specified		Undefined (send email)	Not under active development
Liver X Receptor (LXR) activation leads to liver steatosis	adjacent	High	Not Specified	John Frisch (send email)	Under development: Not open for comment. Do not cite

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
Mus musculus	Mus musculus	Moderate	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	Moderate

Life Stage Applicability

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

Term	Evidence
Adult	High
Juvenile	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

De novo fatty acid synthesis is a main pathway broadly accepted as a mechanism for accumulation of triglycerides in cells. Chemical stressors or alteration of gene expression levels can trigger increased fatty acid influx, as well as changes to membrane permeability and membrane proteins that facilitate fatty acid transport.

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

This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. Support for this KER is referenced in publications cited in the originating work of Landesmann et al. (2012) and Negi et al. (2021).

Evidence Supporting this KER

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

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

The biological plausibility linking increased fatty acid synthesis to accumulation of triglycerides is strong, as a main pathway conserved across taxa.

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

Species	Duration	Dose	Increased FA synthesis?	Increased triglyceride?	Summary	Citation
Human (Homo sapiens), lab mice (Mus musculus)	Up to 7 days	1 μM, 5 μM, and 10 uM T0901317, T0314407 (LXR agonists) for HEK293 cells, 5, 50 mg/kg bdwt T0901317 for mice	Yes	Yes	Increased CYP7A1, SCD-1, and SREBP-1 gene expression vs control in HEK293 cells and C57BL/6 mice, genes linked with fatty acid synthesis, with correlated increases in triglycerides, phospholipids, and HDL cholesterol in a dose-dependent manner.	Schultz et al. (2000)
Lab mice (Mus mucsculus)	4 days	10 mg/kg/day T0901317 (LXR agonist)	Yes	Yes	Lab mice exposed to 10 mg/kg/day T0901317 had increased gene expression of SRBEP, ACC, FAS, genes linked with fatty acid synthesis, and correlated increased triglycerides, cholesterol, fatty acid.	Grefhorst et al. (2002)
Human (Homo sapiens), lab rat (Rattus norvegicus)	96 hours	0.3, 3, 30 nm Insulin plus 2 uM GW3965 (LXR agonist)	Yes	Yes	Increased SREBP-1c, FASN, SCD1 gene expression vs control in human and rat cells, with correlated increases in fatty acid synthesis, pointing to increased de novo lipogenesis, in a dose-dependent manner.	Kotokorpi et al. (2007)

In empirical studies, the link between increased fatty acid synthesis and accumulation of triglycerides is generally inferred. Increased expression of genes and/or signaling molecules known to facilitate fatty acid synthesis, and corresponding increases in triglyceride content in cells, are correlated to show evidence that increases are due to increased synthesis rather than alternative pathways. Angrish et al. (2016) review genes, signaling molecules, and chemical stressors linked to increased fatty acid synthesis, as well as other pathways leading to accumulation of triglycerides in cells.

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

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

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

Life Stage: All life stages with a liver. Older individuals are more likely to manifest this adverse outcome pathway (adults > juveniles) due to accumulation of triglycerides.

Sex: Applies to both males and females.

Taxonomic: Appears to be present broadly in vertebrates, with most representative studies in mammals (humans, lab mice, lab rats).

References

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

Angrish, M.M., Kaiser, J.P., McQueen, C.A., and Chorley, B.N. 2016. Tipping the balance: Hepatotoxicity and the 4 apical key events of hepatic steatosis. Toxicological Sciences 150(2): 261–268.

Grefhorst, A., Elzinga, B.M., Voshol, P.J., Plösch, T., Kok, T., Bloks, V.W., van der Sluijs, F.H., Havekes, L.M., Romijn, J.A., Verkade, H.J., and Kuipers, F. 2002. Stimulation of Lipogenesis by Pharmacological Activation of the Liver X Receptor Leads to Production of Large, Triglyceride-rich Very Low Density Lipoprotein Particles. The Journal of Biological Chemistry 277(37): 34182–34190.

Kotokorpi, P., Ellis, E., Parini, P., Nilsson, L.-M., Strom, S., Steffensen, K.R., Gustafsson, J.-A., and Mode, A. 2007. Physiological Differences between Human and Rat Primary Hepatocytes in Response to Liver X Receptor Activation by 3-[3-[N-(2-Chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy]phenylacetic Acid Hydrochloride (GW3965). Molecular Pharmacology 72(4): 947-955.

Landesmann, B., Goumenou, M., Munn, S., and Whelan, M. 2012. Description of Prototype Modes-of-Action Related to Repeated Dose Toxicity. European Commission Report EUR 25631, 49 pages. https://op.europa.eu/en/publication-detail/-/publication/d2b09726-8267-42de-8093-8c8981201d65/language-en

Negi, C.K., Bajard, L., Kohoutek, J., and Blaha, L. 2021. An adverse outcome pathway based in vitro characterization of novel flame retardants-induced hepatic steatosis. Environmental Pollution 289: 117855.

Schultz, J.R., Tu, H., Luk, A., Repa, J.J., Medina, J.C., Li, L., Schwendner, S., Wang, S., Thoolen, M., Mangelsdorf, D.J., Lustig, K.D., and Shan, B. 2000. Role of LXRs in control of lipogenesis. Genes and Development 14:2831–2838.