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: 2073

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, PPARα leads to Decreased, cholesterol

Upstream event

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

Activation, PPARα

Downstream event

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

Decreased, cholesterol

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
PPARalpha Agonism Leading to Decreased Viable Offspring via Decreased 11-Ketotestosterone	adjacent	High	Low	Jennifer Olker (send email)	Open for citation & comment

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
teleost fish	teleost fish	High	NCBI
Homo sapiens	Homo sapiens	High	NCBI
mice	Mus sp.	High	NCBI
mammals	mammals	Moderate	NCBI

Sex Applicability

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

Sex	Evidence
Male	High
Female	Moderate

Life Stage Applicability

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

Term	Evidence
Adults	High

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

PPARα is a nuclear receptor. With an agonist it promotes transcription of many genes, several of which are involved in cholesterol transport and metabolism (reviewed in Rakhshandehroo et al., 2010).

Hydrophobic lipid molecules (such as cholesterol, cholesteryl ester, and triglycerides) are transported in the aqueous plasma of organisms by forming lipoprotein complexes with apolipoproteins. There are different groups of lipoproteins which use different apolipoproteins and ratios of lipids: low-density (LDL), very low-density (VLDL), and high density (HDL).

Fibrates are a class of drug that agonize PPARα to lower LDL and VLDL while slightly increasing HDL in humans (Singh & Correa, 2020).

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

See below.

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 are 4 proposed mechanisms through which PPARα agonists [fibrates] lower cholesterol in humans (Staels et al., 1998; Chruściel et al., 2015):

Increasing lipoprotein lipase (LPL) and decreasing its inhibitor, APOC3. LPL catabolizes triglycerides in VLDL which lowers the amount VLDL.
Formation of LDL with a higher affinity for the LDL receptor resulting in increased cellular uptake and breakdown of LDL.
Reduced cholesterol ester transfer protein (CEPT) expression. CEPT transfers cholesteryl ester and triglycerides between HDL and VLDL
Increased APOA1 and APOA2, the protein components of HDL, in the liver causing increased production of HDL.

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

Speies	PPARα Agonist	Total CHL	HDL	LDL	VLDL	Citation
Adult Nile tilapia (O. niloticus)	200 mg fenofibrate/kg BW for 4 weeks	decreased	increased	n.s.	--	Ning et al. 2017
Juvenile female rainbow trout (O. mykiss)	100 mg gemfibrozil/kg BW every 3 days for 15 days	-22%	-27%	-34%	-58%	Prindiville et al. 2011
Medaka (O. latipes) embryos	0.04 – 3.7 mg gemfibrozil /L for 155 days	n.s.	--	--	--	Lee et al. 2019
Medaka (O. latipes) adults	0.04 – 3.7 mg gemfibrozil /L for 21 days	n.s. (females) decreased (males)	--	--	--	Lee et al. 2019
Adult zebrafish (D. rerio)	16 mg gemfibrozil/kg BW per day for 30 days	-15% (females) -19% (males)	--	--	--	Al-Habsi et al. 2016
Adult Male Zebrafish (D. rerio)	35, 667, & 1428 mg bezafibrate/kg BW for 48 hours, 7 days, & 21 days	-30% by 21 days, all doses	--	--	--	Velasco-Santamaría et al. 2011
Juvenile grass carp (C. idella) fed HFD	100 mg fenofibrate/kg BW per day for 2 weeks	-22%	n.s.	-45%	--	Du et al. 2008
Adult grass carp (C. idella) fed HFD or HCD	50 mg clofibrate/kg BW per day for 4 weeks	-28% (both)	-9% (HCD) -16% (HFD)	-23% (HCD) -34% (HFD)	--	Guo et al. 2015
Adult fathead minnow (P. promelas)	1 mg/L clofibric acid for 21 days	Decreased (females) n.s. (males)	n.s.	n.s.	--	Runnalls et al. 2007
Juvenile Turbot (S. maximus)	5 or 50 mg WY-14,643/kg BW for 7 or 21 days	decreased	decreased	--	--	Urbatzka et al. 2015

Table 1: Concordance Table for Teleost Fish. Body Weight (BW), Not Significant (n.s.), Cholesterol (CHL), High Fat Diet (HFD), High Carbohydrate Diet (HCD)

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

Although humans taking fibrate medications show lowed LDL and VLDL but slightly increased HDL, this pattern is not seen in fish (Prindiville et al., 2011). The exact reason(s) why is not well understood.

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 factors haven't been evaluated yet.

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

See below

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

After a 7 day exposure to bezafibrate (BZF), male zebrafish exposed to 1.7 mg BZF/g food showed no significant decrease in plasma cholesterol (p>0.05). However, those exposed to 33 and 70 mg BZF/g food showed a 25 and 48% reduction, respectively, in plasma cholesterol (p=0.04 and p<0.001, respectively) (Velasco-Santamaría et al., 2011).

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

Lowered cholesterol in adult male zebrafish due to bezafibrate exposure can be seen after 7 days, but not after just 48 hours (Velasco-Santamaría et al., 2011).

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

Feedback/feedforward loops haven't been evaluated yet.

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

TAXONOMIC APPLICABILITY

The understanding of the effects of PPARα agonists on cholesterol primarily comes from studies on mice and humans to develop pharmaceuticals. However, lowered cholesterol in response to a PPARα agonist occurs in other mammals including rats, dogs, and guinea pigs at low, non-toxic doses (Meyer et al., 1999).

There are several studies showing that in fish PPARα agonism decreases cholesterol via the same mechanisms as in humans:

LPL is conserved in zebrafish (NCBI). It is increased in several fish species exposed to PPARα agonists (Prindiville et al., 2011; Teles et al., 2016; Guo et al., 2015)
LDL is decreased in several fish species exposed to PPARα agonists (see Table 1)
CETP is conserved in zebrafish (NCBI)
APOA1 is conserved in zebrafish (NCBI). However, results are mixed on the effects of PPARα agonists on APOA1 (Corcoran et al., 2015; Teles et al., 2016) and HDL (see table 1) . In mice APOA1 is not regulated by PPARα (Staels & Auwerx, 1998), so this may be the case in fish.

SEX APPLICABILITY

Male and female mice show different effects in several endpoints, including total cholesterol, in response to fibrate administration. This is likely due to estrogen partially and indirectly inhibiting PPARα (Yoon, 2010; Jeong & Yoon, 2012). In fish, males and females often show differing effects on cholesterol (Lee et al., 2019; Runnalls et al., 2007).

References

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

Al-Habsi, A.A., A. Massarsky, T.W. Moon (2016) “Exposure to gemfibrozil and atorvastatin affects cholesterol metabolism and steroid production in zebrafish (Danio rerio)”, Comparative Biochemistry and Physiology, Part B, Vol. 199, Elsevier, pp. 87-96. http://dx.doi.org/10.1016/j.cbpb.2015.11.009

Chruściel, P. et al. (2015) “Statins and fibrates: Should they still be recommended?”, in Combination Therapy in Dyslipidemia, Springer, pp. 11-23. doi: 10.1007/978-3-319-20433-8_2

Corcoran, J. et al. (2015) “Effects of the lipid regulating drug clofibric acid on the PPARα-regulated gene transcript levels in common carp (Cyprinus carpio) at pharmacological and environmental exposure levels”, Aquatic Toxicology, Vol. 161, Elsevier, pp. 127-137. http://dx.doi.org/10.1016/j.aquatox.2015.01.033

Du, Z. et al. (2008) “Hypolipidaemic effects of fenofibrate and fasting in the herbivorous grass carp (Ctenopharyngodon Idella) fed a high-fat diet”, British Journal of Nutrition, Vol. 100, Cambridge University Press, pp. 1200-1212. doi:10.1017/S0007114508986840

Guo, X. et al. (2015) “Effects of lipid-lowering pharmaceutical clofibrate on lipid and lipoprotein metabolism of grass carp (Ctenopharyngodon idellal Val.) fed with the high non-protein energy diets”, Fish Physiology and Biochemistry, Vol. 41, Springer, pp. 331-343. doi: 10.1007/s10695-014-9986-8

Jeong, S. & M. Yoon (2012) “Inhibition of the actions of peroxisome proliferator-activated receptor α on obesity by estrogen”, Obesity, Vol. 15(6), Wiley, pp. 1430-1440. https://doi.org/10.1038/oby.2007.171

Lee, G. et al. (2019) “Effects of gemfibrozil on sex hormones and reproduction related performances of Oryzias latipes following long-term (155 d) and short-term (21 d) exposure”, Ecotoxicology and Environmental Safety, Vol. 173, Elsevier, pp. 174-181. https://doi.org/10.1016/j.ecoenv.2019.02.015

Meyer, K. et al. (1999) “Species difference in induction of hepatic enzymes by BM17.0744, an activator of peroxisome proliferator-activated receptor alpha (PPARα)”, Molecular Toxicology, Vol. 73, Springer-Verlag, pp. 440-450. https://doi.org/10.1007/s002040050633

Ning, L. et al. (2017) “Nutritional background changes the hypolipidemic effects of fenofibrate in Nile tilapia (Oreochromis niloticus)”, Scientific Reports, Vol. 7(41706), Nature. https://doi.org/10.1038/srep41706

Prindiville, J.S. et al. (2011) “The fibrate drug gemfibrozil disrupts lipoprotein metabolism in rainbow trout”, Toxicology and Applied Pharmacology, Vol. 251, Elsevier, pp. 201-238. doi:10.1016/j.taap.2010.12.013

Rakhshandehroo, M. et al. (2010) “Peroxisome Proliferator-Activated Receptor Alpha Target Genes”, PPAR Research, Vol. 2010, Hindawi, https://doi.org/10.1155/2010/612089

Runnalls, T. J., D. N. Hala, J. S. Sumpter (2007) “Preliminary studies into the effects of the human pharmaceutical clofibric acid on sperm parameters in adult fathead minnow”, Aquatic Toxicology, Vol. 84, Elsevier, pp. 111-118. doi:10.1016/j.aquatox.2007.06.005

Singh, G. and R. Correa (2020) “Fibrate Medications”, in StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK547756/

Staels, B. & J. Auwerx (1998) “Regulation of apo A-I gene expression by fibrates”, Atherosclerosis, Vol. 137, Elsevier, pp. s19-23. https://doi.org/10.1016/S0021-9150(97)00313-4

Staels, B. et al. (1998) “Mechanism of action of fibrates on lipid and lipoprotein metabolism”, Cardiovascular Drugs, Vol. 98(19), American Heart Association, pp. 2088-2093.

Teles, M. et al. (2016) “Evaluation of gemfibrozil effects on a marine fish (Sparus aurata) combining gene expression with conventional endocrine and biochemical endpoints”, Journal of Hazardous Materials, Vol. 318, Elsevier, pp. 600-607. http://dx.doi.org/10.1016/j.jhazmat.2016.07.044

Urbatzka, R. et al. (2015) “Effects of the PPARα agonist WY-14,643 on plasma lipids, enzymatic activities and mRNA expression of lipid metabolism genes in a marine flatfish, Scophthalmus maximus”, Aquatic Toxicology, Vol. 164, Elsevier, pp. 155-162. http://dx.doi.org/10.1016/j.aquatox.2015.05.004

Velasco-Santamaría, Y.M. et al. (2011) “Bezafibrate, a lipid-lowering pharmaceutical, as a potential endocrine disruptor in male zebrafish (Danio rerio)”, Aquatic Toxicology, Vol. 105, Elsevier, pp. 107-118. doi:10.1016/j.aquatox.2011.05.018

Yoon, M (2010) “PPARα in Obesity: Sex Differences and Estrogen Involvement”, PPAR Research, Vol. 2010, Hindawi, https://doi.org/10.1155/2010/584296