API

Relationship: 2073

Title

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Activation, PPARα leads to Decreased, cholesterol

Upstream event

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Activation, PPARα

Downstream event

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Decreased, cholesterol

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
PPARalpha Agonism Impairs Fish Reproduction adjacent High Not Specified

Taxonomic Applicability

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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

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Sex Evidence
Male High
Female Moderate

Life Stage Applicability

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Term Evidence
Adults High

Key Event Relationship Description

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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 Supporting this KER

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See below.

Biological Plausibility

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

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

Empirical Evidence

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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)

--

--

--

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

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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. 

Quantitative Understanding of the Linkage

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See below

Response-response Relationship

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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

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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 modulating factors

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Modulating factors haven't been evaluated yet.

Known Feedforward/Feedback loops influencing this KER

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Feedback/feedforward loops haven't been evaluated yet.

Domain of Applicability

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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: 

  1. 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)
  2. LDL is decreased in several fish species exposed to PPARα agonists (see Table 1)
  3. CETP is conserved in zebrafish (NCBI)
  4. 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

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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