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Event: 2225

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Disrupted Lipid Storage

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
eukaryotic cell

Organ term

Organ term
liver

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
lipid storage		disrupted

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
PFOS binding to PPARs leads to liver steatosis	KeyEvent	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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Vertebrates	Vertebrates	High	NCBI

Life Stages

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

Life stage	Evidence
Embryo	Moderate
Juvenile	High
Adult, reproductively mature	High

Sex Applicability

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

Term	Evidence
Male	High
Female	Moderate

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

This Key Event describes the disruption of normal lipid storage in liver cells. 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). An example of an event that can cause disrupted lipid storage is the binding of stressor ligands to the PPAR isoforms with either agonist or antagonist interactions which can lead to effects on lipid storage and transport (Dixon et al. 2021). PPARγ over expression results in promotes storage of lipids in the liver and thus exacerbates hepatic steatosis (Yu et al. 2003; Patsouris et al. 2006). Conversely, deletion of PPARα resulted in an increased liver lipid (Patsouris et al. 2006). Wang et al. (2003) demonstrated that PPARβ/δ deficient mice had increased obesity which, while potentially not a function of improper lipid storage, underpins the importance of all PPAR isoforms in proper lipid homeostasis. Evidence of disruption of lipogenesis at the transcriptional level has also been observed across multiple studies using PFAS as the stressor (Tse et al. 2016; Cui et al. 2017; Huck et al. 2018; Liu et al. 2019; Martinez 2019; Yi et al. 2019; Louisse et al. 2020; Wang et al. 2022a).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

There are numerous methodologies available for measuring disrupted lipid storage in the liver cells. Fatty acids and other lipid species can be measure directly or measured globally using lipidomic methodologies (Wang et al. 2022; Albers et al. 2024), and histopathology can confirm lipid deposits in liver sections (Huck et al. 2018; Wang et al. 2022). Also, targeted or global gene expression analyses can reveal disruptions in key genes responsible for proper lipid storage and transport (Tse et al. 2016; Yi et al. 2019; Louisse et al. 2020).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

The conservation of PPAR molecular structure and function among vertebrates (Gust et al 2020) indicates this key event is likely to be conserved among this broad phylogenetic group. Furthermore, PPAR isoforms play a crucial role in lipid metabolism across representative vertebrate species. However, given that species to species variation does exist in structure and specific function, it is important to exercise care when looking to extrapolate across species.

References

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

Albers, J., Mylroie, J., Kimble, A., Steward, C., Chapman, K., Wilbanks, M., Perkins, E. and Garcia-Reyero, N., 2024. Per-and Polyfluoroalkyl Substances: Impacts on Morphology, Behavior and Lipid Levels in Zebrafish Embryos. Toxics, 12(3), p.192.

Cui, Y., Lv, S., Liu, J., Nie, S., Chen, J., Dong, Q., Huang, C. and Yang, D., 2017. Chronic perfluorooctanesulfonic acid exposure disrupts lipid metabolism in zebrafish. Human & experimental toxicology, 36(3), pp.207-217.

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.

Huck, I., Beggs, K. and Apte, U., 2018. Paradoxical Protective Effect of Perfluorooctanesulfonic Acid Against High-Fat Diet–Induced Hepatic Steatosis in Mice. International journal of toxicology, 37(5), pp.383-392.

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.

Liu, S., Yang, R., Yin, N., Wang, Y.L. and Faiola, F., 2019. Environmental and human relevant PFOS and PFOA doses alter human mesenchymal stem cell self-renewal, adipogenesis and osteogenesis. Ecotoxicology and environmental safety, 169, pp.564-572.

Louisse, J., Rijkers, D., Stoopen, G., Janssen, A., Staats, M., Hoogenboom, R., Kersten, S. and Peijnenburg, A., 2020. Perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorononanoic acid (PFNA) increase triglyceride levels and decrease cholesterogenic gene expression in human HepaRG liver cells. Archives of toxicology, 94(9), pp.3137-3155.

Martínez, R., Navarro-Martín, L., Luccarelli, C., Codina, A.E., Raldúa, D., Barata, C., Tauler, R. and Piña, B., 2019. Unravelling the mechanisms of PFOS toxicity by combining morphological and transcriptomic analyses in zebrafish embryos. Science of the Total Environment, 674, pp.462-471.

Patsouris, D., Reddy, J.K., Müller, M. and Kersten, S., 2006. Peroxisome proliferator-activated receptor α mediates the effects of high-fat diet on hepatic gene expression. Endocrinology, 147(3), pp.1508-1516.

Tse, W.K.F., Li, J.W., Tse, A.C.K., Chan, T.F., Ho, J.C.H., Wu, R.S.S., Wong, C.K.C. and Lai, K.P., 2016. Fatty liver disease induced by perfluorooctane sulfonate: Novel insight from transcriptome analysis. Chemosphere, 159, pp.166-177.

Wang, Y.X., Lee, C.H., Tiep, S., Ruth, T.Y., Ham, J., Kang, H. and Evans, R.M., 2003. Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell, 113(2), pp.159-170.

Wang, Q., Huang, J., Liu, S., Wang, C., Jin, Y., Lai, H. and Tu, W., 2022. Aberrant hepatic lipid metabolism associated with gut microbiota dysbiosis triggers hepatotoxicity of novel PFOS alternatives in adult zebrafish. Environment International, 166, p.107351.

Yi, S., Chen, P., Yang, L. and Zhu, L., 2019. Probing the hepatotoxicity mechanisms of novel chlorinated polyfluoroalkyl sulfonates to zebrafish larvae: Implication of structural specificity. Environment international, 133, p.105262.

Yu, S., Matsusue, K., Kashireddy, P., Cao, W.Q., Yeldandi, V., Yeldandi, A.V., Rao, M.S., Gonzalez, F.J. and Reddy, J.K., 2003. Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor γ1 (PPARγ1) overexpression. Journal of Biological Chemistry, 278(1), pp.498-505.