Peroxisome Proliferator Activated receptors (PPARs; NR1C)

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Peroxisome Proliferator Activated Receptors (PPARs; NR1C)

The Peroxisome Proliferator Activated receptors (PPARs; NR1C) belong to steroid/thyroid/retinoid receptor superfamily of transcription factors that respond to specific ligands by altering gene expression in a cell-, developmental- and sex-specific manner. The name of PPAR receptors family was attributed as they were found to be activated in peroxisomes. Peroxisomes (also called microbodies) are organelles that participate in fatty acid metabolism and eliminate toxic peroxides from the cells. Peroxisomes are known to proliferate under a variety of altered physiological and metabolic states mostly under high concentrations of unsaturated and polyunsaturated fatty acids. The PPAR family comprises the types alpha, gamma and delta/beta each with a specific tissue distribution (Issemann & Green, 1990), (Wahli & Desvergne, 1999).

PPAR Structure

From a structural point of view, PPARs display the characteristic organization of nuclear receptors. The N-terminal A/B domain containing a putative ligand independent transactivation function (AF-1) is flanked by the C-domain which binds DNA via a two zinc finger motif. The C-domain is linked by a short hinge domain (D) to the C-terminal ligand-binding domain, also called the E/F domain, which contains the ligand-dependent transactivation function AF-2.

PPAR transcriptional regulation

PPARs are regulating gene expression by forming heterodimers with the retinoid X receptor (RXR) in a ligand dependent manner. The heterodimers activate transcription by binding to consensus DNA sites composed of direct repeats (DRs) of hexameric DNA sequences (AGGNCA) separated by 1bp, termed the peroxisome proliferator response element (PPRE), in the regulatory region of a variety of genes. The unliganded receptors are engaged in large complexes of corepressors and coactivators that can promote repression and activation, according to the promoter context, respectively (Wahli & Desvergne, 1999), (Feige, Gelman, Michalik, Desvergne, & Wahli, 2006), (Michalik et al., 2007), (Viswakarma et al., 2010). To induce full transcriptional activation, ligand binding enhances the recruitment of coactivators contacting the basal transcriptional machinery (Feige et al., 2006). Upon fixation of an agonist, a conformational change in the structure of the ligand-binding domain creates the interface required for interactions with coactivators, such as SRC-1 or CBP/p300, which results in the transactivation of target genes. Similar to other nuclear receptors, the PPARs are phosphoproteins and their transcriptional (the ligand-independent) activity is affected by cross-talk with kinases and phosphatases (Vanden Heuvel, 1999), (Burns & Vanden Heuvel, 2007). PPARs are activated by fatty acids and their derivatives; they are sensors of dietary lipids and regulate carbohydrate metabolism (Wahli & Desvergne, 1999), (Evans, Barish, & Wang, 2004).

PPAR isoforms

Three subtypes, PPARα, PPARβ/δ and PPARγ, have been identified and these subtypes with a high degree of sequence conservation of each subtype across species, have been documented. The DNA binding domains of the three subtypes are 80% identical, while their ligand-binding domains exhibit a lower degree (approx. 65%) of identity. Consistent with this relatively high divergence among the subtype-specific ligand binding domains, differential activation of PPARs by endogenous and exogenous compounds may account for the specific biological activity of the three PPAR subtypes (Wahli & Desvergne, 1999), (Willson, Brown, Sternbach, & Henke, 2000).



References

Burns, K. A., & Vanden Heuvel, J. P. (2007). Modulation of PPAR activity via phosphorylation. Biochimica et Biophysica Acta, 1771(8), 952–60. doi:10.1016/j.bbalip.2007.04.018 Feige, J. N., Gelman, L., Michalik, L., Desvergne, B., & Wahli, W. (2006). From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Progress in Lipid Research, 45(2), 120–59. doi:10.1016/j.plipres.2005.12.002 Issemann, I., & Green, S. (1990). Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature, 347(6294), 645–650. Michalik, L., Zoete, V., Krey, G., Grosdidier, A., Gelman, L., Chodanowski, P., … Michielin, O. (2007). Combined simulation and mutagenesis analyses reveal the involvement of key residues for peroxisome proliferator-activated receptor alpha helix 12 dynamic behavior. The Journal of Biological Chemistry, 282(13), 9666–77. doi:10.1074/jbc.M610523200 Vanden Heuvel, J. P. (1999). Peroxisome proliferator-activated receptors (PPARS) and carcinogenesis. Toxicological Sciences : An Official Journal of the Society of Toxicology, 47(1), 1–8. Viswakarma, N., Jia, Y., Bai, L., Vluggens, A., Borensztajn, J., Xu, J., & Reddy, J. K. (2010). Coactivators in PPAR-Regulated Gene Expression. PPAR Research, 2010. doi:10.1155/2010/250126 Wahli, W., & Desvergne, B. (1999). Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Reviews, 20(5), 649–88. Willson, T. M., Brown, P. J., Sternbach, D. D., & Henke, B. R. (2000). The PPARs: from orphan receptors to drug discovery. Journal of Medicinal Chemistry, 43(4), 527–50.