API

Relationship: 411

Title

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demethylation, PPARg promoter leads to Up Regulation, CD36

Upstream event

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demethylation, PPARg promoter

Downstream event

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Up Regulation, CD36

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Directness Weight of Evidence Quantitative Understanding
LXR activation leading to hepatic steatosis directly leads to Moderate

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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How Does This Key Event Relationship Work

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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.

Weight of Evidence

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Biological Plausibility

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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 Support for Linkage

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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 or Inconsistencies

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Quantitative Understanding of the Linkage

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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).

Evidence Supporting Taxonomic Applicability

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References

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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