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Relationship: 3365

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, Pregnane-X receptor, NR1l2 leads to Decreased, INSIG1 protein activity

Upstream event

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

Activation, Pregnane-X receptor, NR1l2

Downstream event

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

Decreased, INSIG1 protein activity

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
Activation, Pregnane-X receptor, NR1l2 leads to increased plasma low-density lipoprotein (LDL) cholesterol via increased cholesterol synthesis	adjacent	Moderate		John Frisch (send email)	Under development: Not open for comment. Do not cite
Activation, Pregnane-X receptor, NR1l2 leads to increased plasma low-density lipoprotein (LDL) cholesterol via increased PCSK9 protein expression	adjacent	Moderate		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 Do not cite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
mammals	mammals	High	NCBI

Sex Applicability

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

Sex	Evidence
Unspecific	High

Life Stage Applicability

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

Term	Evidence
All life stages	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

Pregnane X receptor (PXR) is a nuclear receptor that, once activated, binds to Retinoid X receptor (RXR), resulting in regulation of target genes, with an important role in maintenance of lipid homeostasis by affecting rates of glucose synthesis, cholesterol synthesis, lipid synthesis, and lipid uptake (Lv et al. 2022). Increased Pregnane X Receptor (PXR) activation results in decreased insulin-induced gene 1 (INSIG1) protein activity, suggested through destabilization of the INSIG1 protein (Karpale et al. 2021; Itkonen et al. 2023), resulting in increased lipid synthesis.

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 Key Event Relationship was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. Itkonen et al. (2023) focused on identifying Adverse Outcome Pathways that linked PXR activation to increased level of plasma low-density lipoprotein (LDL) cholesterol through review of existing literature, and provided initial network analysis.

Cited empirical studies are focused on PXR gene activity and resulting decreased INSIG1 gene and protein expression in mammals, in support of development of AOP 545 for Itkonen et al. (2023) content.

Authors of KER 3365 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.

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

Pregnane X receptor (PXR) and Insulin-induced gene 1 (INSIG1) have been studied in a variety of gene-knockout, toxicant and diet studies designed to disrupt maintenance of lipid homeostasis in laboratory mammals. The relationship between Pregnane X receptor (PXR) and Insulin-induced gene 1 (INSIG1) is plausible but in need of further study as both loci have important roles in regulation of cholesterol synthesis, but several studies showed activation of PXR led to increased expression of INSIG1, the opposite direction from the mechanism predicted by the adverse outcome pathway (Roth et al. 2008; Zhou et al. 2009; Knebel et al. 2019).

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	Activation Pregnane-X receptor?	Decreased INSIG1 activity?	Summary	Citation
Rat (Rattus norvegicus)	28 days	250, 1250, 5000 mg/kg diet Hexabromo-cyclododecane (HBCD).	yes	yes	Male and female rats at all doses had statistically significant increase in PXR gene expression, leading to dose-dependent INSIG1 gene expression, with statistically significant decrease at 5000 mg/kg diet.	Farmahin et al. (2019)
Mouse (Mus musculus)	16 weeks	60% calories from fat (High fat diet) for 15 weeks, 50 mg/kg pregnenolone-16α-carbonitrile.	yes	yes	6 week old C57BL/6 N mice had statistically significant increase in PXR gene expression, leading to statistically significant decrease in INSIG1 gene expression.	Karpale et al. (2021)
Mouse (Mus musculus)	28 days	5 percent diet ethanol.	yes	yes	Adult 8 week old male C57BL/6 J mice showed statistically significant increase in PXR gene expression, leading to statistically significant decrease in INSIG1 gene expression.	Huang et al. (2022)

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

Modulating Factor (MF)	MF Specification	Effect(s) on the KER	Reference(s)

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.

Sex: Applies to both males and females.

Taxonomic: Primarily studied in humans and laboratory rodents.

References

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

Farmahin, R., Gannon, A.M., Gegne, R., Rowan-Carrol, A., Kuo, B., Williams, A., Curran, I., and Yauk, C.L. 2019. Hepatic transcriptional dose-response analysis of male and female Fischer rats exposed to hexabromocyclododecane. Food and Chemical Toxicology 133: 110262.

Huang, X., Yang, S., Sun, J., Li, X., Zhou, S.-Y., Shi, J.-S., Liu, J., and Wu, Q. 2022. Transcriptome Analysis of Protection by Dendrobium nobile Alkaloids (DNLA) against Chronic Alcoholic Liver Injury in Mice. Biomedicines 10: 2800.

Itkonen, A., Hakkola, J., and Rysa, J. 2023. Adverse outcome pathway for pregnane X receptor‑induced Hypercholesterolemia. Archives of Toxicology 97: 2861–2877.

Karpale, M. Karajamaki, A.J., Kummu, O., Gylling, H., Hyotylainen, T., Oresic, M., Tolonen, A., Hautajarvi, H., Savolainen, M.J., Ala-Korpela, M., Hukkanen, J., and Hakkola, J. 2021. Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism. British Journal of Pharmacology 178: 2461–2481.

Knebel C., Buhrke T., Sussmuth R., Lampen, A., Marx-Stoelting, P., and Braeuning, A. 2019. Pregnane X receptor mediates steatotic effects of propiconazole and tebuconazole in human liver cell lines. Archives of Toxicology 93:1311–1322.

Lv, Y., Luo, Y.-Y., Ren, H.-W., Li, C.-J., Xiang, Z.-X., and Luan, Z.L. 2022. The role of pregnane X receptor (PXR) in substance metabolism. Frontiers in Endocrinology 13: 959902. Roth, A., Looser, R., Kaufmann, M., Blattler, S.M., Rencurel, F., Huang, W., Moore, D.D., and Meyer, U.A. 2008. Regulatory cross-talk between drug metabolism and lipid homeostasis: Constitutive androstane receptor and pregnane X receptor increase Insig-1 expression. Molecular Pharmacology 73: 1282–1289.

Zhou C., King N., Chen K.Y., and Breslow JL. 2009. Activation of PXR induces hypercholesterolemia in wild-type and accelerates atherosclerosis in apoE deficient mice. Journal of Lipid Research 50(10): 2004–2013.

NOTE: Italics indicate edits from John Frisch October 2024.