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demethylation, PPARg promoter leads to Up Regulation, CD36
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
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
Evidence Supporting this KER
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).
Uncertainties and Inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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