Transcriptional control of physiological and pathological processes by the nuclear receptor PPAR beta/delta

Peroxisome proliferator-activated receptors (PPARs) are a class of transcription factors that belong to the nuclear hormone receptor superfamily, and their activities are dependent on their respective ligands. Since the discovery of PPARα (NR1C1) as a receptor that mediates peroxisome proliferation in rodent hepatocytes in 1990 [1], two other isotypes, PPARβ/δ (NR1C2) and PPARγ (NR1C3), were subsequently identified and characterized [2,3]. Members of the PPAR family have been extensively linked to numerous systemic and cellular activities that range far beyond simply mediating peroxisome proliferation in rodents [4]. Dependent on isotype-specific or shared tissue expression, all three PPARs regulate different or, in some cases, overlapping functions [5]. PPARα and PPARγ have established roles in fatty acid (FA) catabolism and in adipocyte differentiation and lipid storage, respectively, and both are pharmacological targets of FDA-approved drugs for the treatment of numerous metabolic diseases [6,7]. In contrast, no PPARβ/δ ligands are currently used in the treatment of any disease, although small studies on human subjects have used PPARβ/δ ligands to treat metabolic syndrome [8,9]. PPARβ/δ is expressed in numerous tissues [10,11], and many important functions have been attributed to PPARβ/δ in skeletal muscle, adipose tissue, the cardiovascular system, uterine implantation, the gut, the brain, and skin [12]. These factors make PPARβ/δ a very attractive and challenging target, as it is involved in numerous key functions, such as energy metabolism, cellular differentiation and proliferation, tissue repair, and cancer progression. ASTAR (Agency for Sci., Tech. and Research, S’pore) MOE (Min. of Education, S’pore) NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore) Accepted version