PPARs bind a specific element in the promoter region of target genes. The dimerization of PPAR with RXR and the presence of coactivators are neccessary for the transcriptional activity of PPAR responsive element

Nuclear receptors are transcription factors activated by specific ligands which play an important role during cell signalling. They belong to the steroid-thyroid-retinoid receptor superfamily; these include receptors for steroids, thyroid hormone, vitamin A and D derived hormones and some fatty acids. Structurally, they share common features: highly conserved central DNA binding domain (binds receptor to specific DNA sequences – Hormone Response Elements, HRE), ligand binding domain in the COOHterminal region and variable N-terminal domain. Recently, the three-dimensional structure of DNA binding domains of various nuclear receptors have been described1. However, in some nuclear receptors the natural ligand (hormone) has not been identified and therefore the term “orphan” receptors (OR) was suggested a decade ago. Searching for such ligands (hormones) has introduced the concept of “reverse endocrinology”2. A typical example of this approach is the discovery of 9-cis retinoic acid (a metabolite of vitamin A) as a high-affinity ligand for three variants of retinoid X receptors (RXR). This in turn has led to better understanding of the processes regulated by retinoids3. Currently, five families of OR are distinguished: 1. liver X receptor – LXR, 2. pregnane X receptor – PXR, 3. constitutive androstane receptor – CAR, 4. farnesoid X receptor – FXR and 5. peroxisome proliferatoractivated receptors – PPARs. LXR is an oxysterol receptor and regulates the catabolism of excess dietary cholesterol. PXR is activated by many compounds and by binding to a xenobiotic response element in the CYP3A4 gene promoter serves as a xenobiotic sensor. The physiological role of CAR is not clear, however, although it is suggested that like PXR it may play a role in the regulation of steroid homeostasis. FXR is a nuclear bile acid receptor2, 4. Peroxisome Proliferator-Activated Receptors (PPARs) were first cloned from mouse liver in 1990 as the nuclear receptor mediating the effects of many synthetic (industrial and pharmaceutical) compounds called peroxisome proliferators (PPs)5. PPs influence both the size and number of peroxisomes, which perform various metabolic functions (peroxide derived respiration, beta oxidation of fatty acids, cholesterol metabolism, etc.) within the cell. It has been found that three PPAR isoforms exist: PPAR alpha, PPAR delta (also known as NUC1 or PPAR beta) and PPAR gamma. These are encoded by separated genes, perform separate functions and exhibit different tissue localization (Table 1). Like other nuclear receptors, after activation by ligand, PPARs bind a specific element in the promoter region of target genes. The dimerization of PPAR with RXR and the presence of coactivators are neccessary for the transcriptional activity of PPAR responsive element (PPRE) in DNA (Table 2). It is interesting, that not all PPRE in responsive genes mediate increase in transcription. For instance transthyretin, transferrin and/or some apolipoprotein genes are regulated negatively6, 7, 8, 9. There is a wide spectrum of both exogenous and endogenous ligands of PPARs (Table 3) and it has been noted that their interaction with PPARs leads to various functions. PPARs play an important role during rodent PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPARs) IN HEALTH AND DISEASE