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Relationship: 3210

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

Disrupted Lipid Storage leads to Accumulation, Fatty acid

Upstream event

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

Disrupted Lipid Storage

Downstream event

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

Accumulation, Fatty acid

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
Xenobiotic binding to peroxisome proliferator-activated receptors (PPARs) causes dysregulation of lipid metabolism leading to liver steatosis	adjacent	Moderate	Moderate	Erik Mylroie (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 Do not cite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
Vertebrates	Vertebrates	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
Embryo	Moderate
Juvenile	Moderate
Adult, reproductively mature	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

This Key Event Relationship describes how disrupted lipid storage in the liver results in the accumulation of fatty acids. Disruption of lipid storage and transport can be identified by excess accumulation of fatty acids or other lipids in the liver or altered ratios of expected lipid species which can ultimately lead to liver steatosis (Ipsen et al. 2018). Disruption of lipid metabolism through dysregulation of transcriptional control and/or decreased or impaired mitochondrial β-oxidation can result in improper lipid storage and an accumulation of fatty acids in liver cells (Ament et al. 2012; Cherkaoui-Malki et al. 2012; Fromenty 2019; Dixon et al. 2021; Xiao et al. 2021).

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

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

Proper lipid homeostasis is controlled by the balance of lipid influx and efflux as well as the balance between lipogenesis and lipid catabolism (Ipsen et al. 2018; Kloska et al. 2020; Geng et al. 2021; Yoon et al. 2021). Therefore, disruption of this balance via diet, disease, or environmental stressor can lead to the improper storage and transport of lipids in the liver and the subsequent accumulation of fatty acids (Ipsen et al. 2018).

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

There is ample evidence outlining how improper lipid storage and transport can result in the accumulation of fatty acids in the liver (Ipsen et al. 2018). For example, overexpression of a fatty acid transport gene CD36 in mice increased fatty acid uptake and accumulation in livers (Koonen et al. 2007). The over expression of human hepatic lipase (hHL) in mice resulted in increased de novo synthesis of fatty acids and upregulation of fatty acid synthesis genes such as Srebf1, Fasn, Acaca, and Nr1h3 (Cedó et al. 2017). Finally, overexpression of sterol regulatory element–binding proteins (SREBP), which is one of the key regulatory elements in lipid synthesis, resulted in an increase in fatty acid synthesis and fatty acid synthase (Fas) gene expression in mouse livers (Horton et al. 2002).

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

Energy homeostasis is a complex system in vertebrates and controlled via the cross-talk of numerous pathways. Therefore, it is important to understand that factors like age, sex, and the fed state of the organism could all have a direct effect on lipid storage and subsequent fatty acid accumulation in the liver of the target organism.

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

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

Hours to Days

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

Lipid homeostasis is a well-studied biological process integral to vertebrates and invertebrates. The feedforward/feedback loops involved in regulating lipid storage and transport are extensive and present a challenge to properly represent in this KER summary. The authors suggest reading the reviews by Ipsen et al. (2018) and Geng et al. (2021) for comprehensive summaries of feedforward/feedback loops influencing this KER.

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

Lipid storage and transport is a crucial biological function maintained across representative vertebrate species. However, given that species to species variation in genes and specific regulatory mechanisms do exist it is important to exercise care when looking to extrapolate across species.

References

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

Ament, Z., Masoodi, M. and Griffin, J.L., 2012. Applications of metabolomics for understanding the action of peroxisome proliferator-activated receptors (PPARs) in diabetes, obesity and cancer. Genome Medicine, 4, pp.1-12.

Cedó, L., Santos, D., Roglans, N., Julve, J., Pallarès, V., Rivas-Urbina, A., Llorente-Cortes, V., Laguna, J.C., Blanco-Vaca, F. and Escola-Gil, J.C., 2017. Human hepatic lipase overexpression in mice induces hepatic steatosis and obesity through promoting hepatic lipogenesis and white adipose tissue lipolysis and fatty acid uptake. PLoS One, 12(12), p.e0189834.

Cherkaoui-Malki, M., Surapureddi, S., I El Hajj, H., Vamecq, J. and Andreoletti, P., 2012. Hepatic steatosis and peroxisomal fatty acid beta-oxidation. Current Drug Metabolism, 13(10), pp.1412-1421.

Dixon, E.D., Nardo, A.D., Claudel, T. and Trauner, M., 2021. The role of lipid sensing nuclear receptors (PPARs and LXR) and metabolic lipases in obesity, diabetes and NAFLD. Genes, 12(5), p.645.

Fromenty, B., 2019. Inhibition of mitochondrial fatty acid oxidation in drug-induced hepatic steatosis. Liver Research, 3(3-4), pp.157-169.

Geng, Y., Faber, K.N., de Meijer, V.E., Blokzijl, H. and Moshage, H., 2021. How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?. Hepatology international, 15, pp.21-35.

He, X., Gao, J., Hou, H., Qi, Z., Chen, H. and Zhang, X.X., 2019. Inhibition of mitochondrial fatty acid oxidation contributes to development of nonalcoholic fatty liver disease induced by environmental cadmium exposure. Environmental science & technology, 53(23), pp.13992-14000.

Horton, J.D., Goldstein, J.L. and Brown, M.S., 2002. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. The Journal of clinical investigation, 109(9), pp.1125-1131.

Houten, S.M. and Wanders, R.J., 2010. A general introduction to the biochemistry of mitochondrial fatty acid β-oxidation. Journal of inherited metabolic disease, 33, pp.469-477.

Ipsen, D.H., Lykkesfeldt, J. and Tveden-Nyborg, P., 2018. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cellular and molecular life sciences, 75, pp.3313-3327.

Koonen, D.P., Jacobs, R.L., Febbraio, M., Young, M.E., Soltys, C.L.M., Ong, H., Vance, D.E. and Dyck, J.R., 2007. Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity. diabetes, 56(12), pp.2863-2871.

Massart, J., Begriche, K., Buron, N., Porceddu, M., Borgne-Sanchez, A. and Fromenty, B., 2013. Drug-induced inhibition of mitochondrial fatty acid oxidation and steatosis. Current Pathobiology Reports, 1, pp.147-157.

Morris, E.M., Rector, R.S., Thyfault, J.P. and Ibdah, J.A., 2011. Mitochondria and redox signaling in steatohepatitis.

Naguib, G., Morris, N., Yang, S., Fryzek, N., Haynes‐Williams, V., Huang, W.C.A., Norman‐Wheeler, J. and Rotman, Y., 2020. Dietary fatty acid oxidation is decreased in non‐alcoholic fatty liver disease: A palmitate breath test study. Liver International, 40(3), pp.590-597.

Xiao, Y., Kim, M. and Lazar, M.A., 2021. Nuclear receptors and transcriptional regulation in non-alcoholic fatty liver disease. Molecular Metabolism, 50, p.101119.

Yoon, H., Shaw, J.L., Haigis, M.C. and Greka, A., 2021. Lipid metabolism in sickness and in health: Emerging regulators of lipotoxicity. Molecular cell, 81(18), pp.3708-3730.