This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 3218

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

Increase, Liver steatosis leads to Cell injury/death

Upstream event

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

Increase, Liver steatosis

Downstream event

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

Cell injury/death

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
AhR activation leading to liver fibrosis	adjacent	Moderate	Moderate	Xavier COUMOUL (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 Do not cite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

Sex Applicability

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

Life Stage Applicability

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

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

Liver steatosis involves the abnormal accumulation of lipids within hepatocytes, which, when excessive, induces cellular stress through mechanisms such as oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress. These disruptions compromise cell integrity and function, leading to cell death through apoptosis or necrosis. Indeed, empirical evidence supports this relationship (see below also) across various models, including in vitro studies where lipid accumulation triggers reactive oxygen species (ROS) production and cell death, as well as in vivo models of diet-induced steatosis that demonstrate progressive liver damage. Clinically, in patients with non-alcoholic fatty liver disease (NAFLD), a transition from simple steatosis to non-alcoholic steatohepatitis (NASH) involves hepatocyte injury and death, evidenced by histopathological changes and increased biomarkers of liver damage (PMID: 34848246).

The quantitative link between lipid accumulation and cell injury/death shows a dose-dependent relationship, although modulating factors such as the type of lipids, genetic predispositions, and environmental influences can affect the severity and onset of cell damage. Understanding this KER is essential for identifying interventions aimed at mitigating the progression of liver steatosis to irreversible liver injury.

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

Liver steatosis, characterized by excessive accumulation of lipids in hepatocytes, predisposes cells to injury and death due to lipotoxicity. Excessive lipid accumulation leads to oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress. These cellular disturbances compromise membrane integrity, impair energy homeostasis, and activate apoptotic and necrotic pathways, resulting in cell injury and death. Chronic steatosis amplifies inflammatory signaling, creating a self-perpetuating cycle of liver damage (PMID: 37400694).

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

In vitro studies: Hepatocytes exposed to elevated free fatty acid levels (e.g., palmitate) exhibit lipid accumulation followed by markers of oxidative stress (e.g., ROS production) and cell death (apoptosis or necrosis).
Animal models: Rodents fed a high-fat diet show progression from liver steatosis to hepatocyte injury, evidenced by elevated serum alanine aminotransferase (ALT) levels and histological detection of necrotic foci.
Clinical observations: In patients with non-alcoholic fatty liver disease (NAFLD), progression from simple steatosis to non-alcoholic steatohepatitis (NASH) involves significant hepatocyte ballooning (a marker of injury) and cell death

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

Heterogeneity of lipid species: Not all lipid accumulations are equally toxic. For example, triglycerides may serve as inert storage, whereas free fatty acids and ceramides are directly cytotoxic. Same remark regarding the type of fatty acids (saturated ones vs omega3)
Species differences: Rodents and humans may exhibit differences in susceptibility to lipid-induced liver damage.
Temporal dynamics: The time lag between lipid accumulation and detectable cell injury varies across models, complicating predictions.

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

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)
Genetic factors	Variants in genes such as PNPLA3 influence susceptibility to lipid-induced hepatocyte injury.
Dietary factors	Antioxidants or omega-3 fatty acids may mitigate the progression from steatosis to cell death.
Comorbidities	Insulin resistance and chronic inflammation exacerbate steatosis-related cell injury.

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

The relationship between liver steatosis and cell injury/death exhibits a dose-dependent response. Higher levels of lipid accumulation correlate with increased markers of hepatocyte damage, such as ALT, AST, and lactate dehydrogenase (LDH) release. Thresholds for lipid overload beyond which cellular injury becomes inevitable have been proposed in experimental studies but remain context-dependent, influenced by factors like lipid species and duration of exposure.

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

Human : PMID: 32044315
Rat: PMID: 26674288
Mouse : PMID: 36690638

Understanding this KER is critical for the development of interventions targeting early lipid accumulation to prevent downstream liver damage. It also aids in the establishment of biomarkers predictive of NAFLD/NASH progression.

References

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

Schwabe RF, Tabas I, Pajvani UB. Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis. Gastroenterology. 2020 May;158(7):1913-1928. doi: 10.1053/j.gastro.2019.11.311. Epub 2020 Feb 8. PMID: 32044315; PMCID: PMC7682538.

Moravcová A, Červinková Z, Kučera O, Mezera V, Rychtrmoc D, Lotková H. The effect of oleic and palmitic acid on induction of steatosis and cytotoxicity on rat hepatocytes in primary culture. Physiol Res. 2015;64(Suppl 5):S627-36. doi: 10.33549/physiolres.933224. Epub 2015 Dec 15. PMID: 26674288.

Inaba Y, Hashiuchi E, Watanabe H, Kimura K, Oshima Y, Tsuchiya K, Murai S, Takahashi C, Matsumoto M, Kitajima S, Yamamoto Y, Honda M, Asahara SI, Ravnskjaer K, Horike SI, Kaneko S, Kasuga M, Nakano H, Harada K, Inoue H. The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice. Nat Commun. 2023 Jan 23;14(1):167. doi: 10.1038/s41467-023-35804-w. PMID: 36690638; PMCID: PMC9871012.

Eti NA, Flor S, Iqbal K, Scott RL, Klenov VE, Gibson-Corley KN, Soares MJ, Ludewig G, Robertson LW. PCB126 induced toxic actions on liver energy metabolism is mediated by AhR in rats. Toxicology. 2022 Jan 30;466:153054. doi: 10.1016/j.tox.2021.153054. Epub 2021 Nov 27. PMID: 34848246; PMCID: PMC8748418.

Hammerich L, Tacke F. Hepatic inflammatory responses in liver fibrosis. Nat Rev Gastroenterol Hepatol. 2023 Oct;20(10):633-646. doi: 10.1038/s41575-023-00807-x. Epub 2023 Jul 3. PMID: 37400694.