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Relationship: 3219

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

Activation, AhR leads to Increase, Liver steatosis

Upstream event

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

Activation, AhR

Downstream event

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

Increase, Liver steatosis

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	High	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 Do not cite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

Term	Scientific Term	Evidence	Link
human	Homo sapiens	Moderate	NCBI
Rattus norvegicus	Rattus norvegicus	High	NCBI
Mus musculus	Mus musculus	High	NCBI

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

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates cellular responses to environmental toxins, dietary components, and endogenous metabolites. Upon ligand binding, AhR translocates to the nucleus, dimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT), and binds to xenobiotic response elements (XREs) in the promoter regions of target genes. While its primary function involves detoxification through the regulation of cytochrome P450 enzymes (e.g., CYP1A1, CYP1B1), chronic or excessive AhR activation is implicated in metabolic disorders, including liver steatosis (PMID: 34830313, PMID: 37284280).

AhR activation modulates lipid homeostasis through the upregulation of key lipogenic pathways. It regulates the expression of sterol regulatory element-binding protein 1c (SREBP-1c), a master regulator of fatty acid and triglyceride synthesis (PMID: 29694888). Increased SREBP-1c expression enhances the transcription of lipogenic enzymes, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), leading to de novo lipogenesis (PMID: 21029304). Concurrently, AhR increases the expression of CD36, a key transporter of fatty acids, which contributes to the import of these molecules in the cytoplasm and subsequently to de novo lipogenesis (PMID: 20303349).

AhR activation also drives liver steatosis by inducing inflammatory responses. It promotes the production of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) (PMID: 27713108). This inflammatory milieu exacerbates hepatic lipid accumulation by impairing insulin signaling, which further upregulates SREBP-1c activity. Additionally, AhR activation increases the production of reactive oxygen species (ROS), leading to oxidative stress, lipid peroxidation, and hepatocyte injury, all of which contribute to the pathogenesis of steatosis (PMID: 34830313). Furthermore, AhR-mediated repression of fibroblast growth factor 21 (FGF21), a hormone critical for lipid metabolism and insulin sensitivity, has been implicated in exacerbating steatosis (PMID: 27226639).

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

There is a mechanistical relationship between both KEs (see ‘Key Event Relationship Description’)

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 temporal concordance as AhR activation leads to adaptative responses in the liver including metabolic switch. In tumor cells, AhR activation is associated with a Warburg effect and increased glycolytic activity; subsequently, mitochondrial metabolism is decreased which is consistent with liver steatosis that depends on lipid catabolism mainly observed in the mitochondrial matrix with beta-oxidation (PMID: 26582802).

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

There are no inconsistencies

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

There are no quantitative data.

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: 31401392
Rat: PMID: 34848246
Mouse : PMID: 34830313, PMID: 27713108

References

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

Fling RR, Zacharewski TR. Aryl Hydrocarbon Receptor (AhR) Activation by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Dose-Dependently Shifts the Gut Microbiome Consistent with the Progression of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci. 2021 Nov 18;22(22):12431. doi: 10.3390/ijms222212431. PMID: 34830313; PMCID: PMC8625315.

Patil NY, Friedman JE, Joshi AD. Role of Hepatic Aryl Hydrocarbon Receptor in Non-Alcoholic Fatty Liver Disease. Receptors (Basel). 2023 Mar;2(1):1-15. doi: 10.3390/receptors2010001. Epub 2023 Jan 4. PMID: 37284280; PMCID: PMC10240927.

Krishnan S, Ding Y, Saedi N, Choi M, Sridharan GV, Sherr DH, Yarmush ML, Alaniz RC, Jayaraman A, Lee K. Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages. Cell Rep. 2018 Apr 24;23(4):1099-1111. doi: 10.1016/j.celrep.2018.03.109. Erratum in: Cell Rep. 2019 Sep 17;28(12):3285. doi: 10.1016/j.celrep.2019.08.080. PMID: 29694888; PMCID: PMC6392449.

Ferré P, Foufelle F. Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes Obes Metab. 2010 Oct;12 Suppl 2:83-92. doi: 10.1111/j.1463-1326.2010.01275.x. PMID: 21029304.

Lee JH, Wada T, Febbraio M, He J, Matsubara T, Lee MJ, Gonzalez FJ, Xie W. A novel role for the dioxin receptor in fatty acid metabolism and hepatic steatosis. Gastroenterology. 2010 Aug;139(2):653-63. doi: 10.1053/j.gastro.2010.03.033. Epub 2010 Mar 17. PMID: 20303349; PMCID: PMC2910786.

Duval C, Teixeira-Clerc F, Leblanc AF, Touch S, Emond C, Guerre-Millo M, Lotersztajn S, Barouki R, Aggerbeck M, Coumoul X. Chronic Exposure to Low Doses of Dioxin Promotes Liver Fibrosis Development in the C57BL/6J Diet-Induced Obesity Mouse Model. Environ Health Perspect. 2017 Mar;125(3):428-436. doi: 10.1289/EHP316. Epub 2016 Oct 7. PMID: 27713108; PMCID: PMC5332187.

Girer NG, Murray IA, Omiecinski CJ, Perdew GH. Hepatic Aryl Hydrocarbon Receptor Attenuates Fibroblast Growth Factor 21 Expression. J Biol Chem. 2016 Jul 15;291(29):15378-87. doi: 10.1074/jbc.M116.715151. Epub 2016 May 25. PMID: 27226639; PMCID: PMC4946947.

Xia H, Zhu X, Zhang X, Jiang H, Li B, Wang Z, Li D, Jin Y. Alpha-naphthoflavone attenuates non-alcoholic fatty liver disease in oleic acid-treated HepG2 hepatocytes and in high fat diet-fed mice. Biomed Pharmacother. 2019 Oct;118:109287. doi: 10.1016/j.biopha.2019.109287. Epub 2019 Aug 8. PMID: 31401392.

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.