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Relationship: 411

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

demethylation, PPARg promoter leads to Up Regulation, CD36

Upstream event

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

demethylation, PPARg promoter

Downstream event

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

Up Regulation, CD36

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
LXR activation leading to hepatic steatosis	adjacent	Moderate		Agnes Aggy (send email)	Not under active development

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

After ligand binding, hepatic PPARγ heterodimerizes with retinoid X receptor and activates target genes involved in lipid storage and metabolism, such as CD36. Subsequently, the CD36 is up-regulated , next the CD36 translocates to the plasma membrane where it can markedly increase the hepatic uptake of fatty acids (FAs) from the circulation.

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

PPARγ is expressed in the liver (Braissant, Foufelle, Scotto, Dauça, & Wahli, 1996) and regulates CD36 gene transcriptional activation through binding to the peroxisome-proliferator-responsive elements (PPREs) in the promoter region (Teboul et al., 2001). The CD36 is also regulated by several other ligand-sensing and lipogenic transcriptional factors, such as pregnane X receptor, liver X receptor (Zhou et al., 2008) and the aryl hydrocarbon receptor (He, Lee, Febbraio, & Xie, 2011).

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

Include consideration of temporal concordance here

Mice

• on high fat diet the levels of PPARγ and CD 36 were increased, additionally inhibition of PPARγ resulted in reduction of CD36 whereas overexpression of receptor lead to overexpression of CD36 protein (Yamazaki, Shiraishi, Kishimoto, Miura, & Ezaki, 2011).

• overexpression of PPARγ2 resulted in a marked induction of s PPARγ target gene CD36 in vivo and in vitro in primary hepatocytes (Lee et al., 2012).

Compound/diet	PPARγ activation	up-regulation of CD36	species	Study type	Reference
diet rich in saturated fat (fed butter or safflower oil as a high-fat (HF)	increase of PPAR γ mRNA (at 4 and 10 weeks) and PPAR γ protein at 4 weeks)	mRNA CD36 (at 4 and 10 weeks)	C57BL/6J mice	In vivo	(Yamazaki et al., 2011)
none	Overexpression of PPARγ	mRNA CD36	C57BL/6 mice/ C3H	In vivo	(Lee et al., 2012)
none	Overexpression of PPARγ	mRNA CD36	C57BL/6 mice/ C3H	In vitro	(Lee et al., 2012)
troglitazone	increase of PPAR γ mRNA	mRNA CD36	C57BL/6J	In vivo	(Memon et al., 2000)

Table 1 Summary of the empirical support for the KER.

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

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

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?

Contradictory studies have been published investigating the role of PPARγ in the activation of CD36 gene. In contrast to previously reported direct involvement of PPAR in regulation of CD36: Sato et al. suggested an indirect mechanism (Sato, Kuriki, Fukui, & Motojima, 2002).

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

References

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

Braissant, O., Foufelle, F., Scotto, C., Dauça, M., & Wahli, W. (1996). Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology, 137(1), 354–66.

He, J., Lee, J. H., Febbraio, M., & Xie, W. (2011). The emerging roles of fatty acid translocase/CD36 and the aryl hydrocarbon receptor in fatty liver disease. Experimental Biology and Medicine (Maywood, N.J.), 236(10), 1116–21. doi:10.1258/ebm.2011.011128

Lee, Y. J., Ko, E. H., Kim, J. E., Kim, E., Lee, H., Choi, H., … Kim, J. (2012). Nuclear receptor PPARγ-regulated monoacylglycerol O-acyltransferase 1 (MGAT1) expression is responsible for the lipid accumulation in diet-induced hepatic steatosis. Proceedings of the National Academy of Sciences of the United States of America, 109(34), 13656–61. doi:10.1073/pnas.1203218109

Memon, R. A., Tecott, L. H., Nonogaki, K., Beigneux, A., Moser, A. H., Grunfeld, C., & Feingold, K. R. (2000). Up-regulation of peroxisome proliferator-activated receptors (PPAR-alpha) and PPAR-gamma messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in the li. Endocrinology, 141(11), 4021–31. doi:10.1210/endo.141.11.7771

Sato, O., Kuriki, C., Fukui, Y., & Motojima, K. (2002). Dual promoter structure of mouse and human fatty acid translocase/CD36 genes and unique transcriptional activation by peroxisome proliferator-activated receptor alpha and gamma ligands. The Journal of Biological Chemistry, 277(18), 15703–11. doi:10.1074/jbc.M110158200

Teboul, L., Febbraio, M., Gaillard, D., Amri, E. Z., Silverstein, R., & Grimaldi, P. A. (2001). Structural and functional characterization of the mouse fatty acid translocase promoter: activation during adipose differentiation. The Biochemical Journal, 360(Pt 2), 305–12.

Yamazaki, T., Shiraishi, S., Kishimoto, K., Miura, S., & Ezaki, O. (2011). An increase in liver PPARγ2 is an initial event to induce fatty liver in response to a diet high in butter: PPARγ2 knockdown improves fatty liver induced by high-saturated fat. The Journal of Nutritional Biochemistry, 22(6), 543–53. doi:10.1016/j.jnutbio.2010.04.009

Zhou, J., Febbraio, M., Wada, T., Zhai, Y., Kuruba, R., He, J., … Xie, W. (2008). Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology, 134(2), 556–67. doi:10.1053/j.gastro.2007.11.037