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Received Sep 29, 2017; Revised Jan 22, 2018; Accepted Feb 5, 2018
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
1. Introduction
Peroxisome proliferator-activated receptor beta/delta (PPARß/δ) is a lipid-activated transcription factor, which is a member of the nuclear receptors (NR) superfamily that regulates the activation or silencing of several target genes. PPARß/δ is ubiquitously expressed in humans, although it is mainly found in the skin, placenta, brain, liver, kidneys, spleen, fat skeletal muscle, and digestive tube [1–3].
PPARß/δ is involved in some metabolic pathways such as energy metabolism, homeostasis, adipogenesis, and lipid metabolism [4–6]. Several studies have suggested that PPARß/δ modulation by agonists regulates food intake, body weight, insulin sensitivity, adiposity, and body mass [5, 7]. It has also been associated with diverse physiopathological processes, such as inflammation, obesity, dyslipidemia, diabetes, cancer, and cardiovascular diseases [6, 8–10]. PPARß/δ also has described extra-metabolic roles including neuroprotective effects against brain diseases, such as multiple sclerosis, strokes, Alzheimer’s disease, and Parkinson’s disease, and acts in cell differentiation and proliferation, immune regulation, oxidative stress, and skin biology [2, 3, 11].
The diversity in PPARß/δ function has been related to its ability to accommodate and bind different ligands in its ligand binding domain (LBD), with a wide range of natural and synthetic ligands. Among the natural ligands, there are fatty acids, prostaglandins, and leukotrienes [12, 13]. Several high affinity and subtype-specific PPARß/δ agonists have been developed and submitted for clinical trials for the treatment of metabolic diseases [1, 14]; however no ligand has been made available for clinical use.
Due to the high number of people affected by PPARß/δ-related disorders, the development of specific ligands to modulate the receptor activity becomes of great importance. Here, we developed and set up a suitable, cheaper, and robust screening pipeline for the better identification of PPARß/δ agonists. In the first step of this pipeline, we optimized the cell-based transactivation assay to be 1 to 2 days shorter and with the use of less reagents than the previously described ones, significantly reducing the costs in time and money for...