New Insights into the Role of PPARγ in Skin Physiopathology

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor expressed in many tissues, including skin, where it is essential for maintaining skin barrier permeability, regulating cell proliferation/differentiation, and modulating antioxidant and inflammatory responses upon ligand binding. Therefore, PPARγ activation has important implications for skin homeostasis. Over the past 20 years, with increasing interest in the role of PPARs in skin physiopathology, considerable effort has been devoted to the development of PPARγ ligands as a therapeutic option for skin inflammatory disorders. In addition, PPARγ also regulates sebocyte differentiation and lipid production, making it a potential target for inflammatory sebaceous disorders such as acne. A large number of studies suggest that PPARγ also acts as a skin tumor suppressor in both melanoma and non-melanoma skin cancers, but its role in tumorigenesis remains controversial. In this review, we have summarized the current state of research into the role of PPARγ in skin health and disease and how this may provide a starting point for the development of more potent and selective PPARγ ligands with a low toxicity profile, thereby reducing unwanted side effects.

Keywords: PPARs; inflammatory skin disease; lipids; sebaceous gland; skin cancer; skin physiology.

Figure 3

Representative PPARγ activators. Chemical structures of the most tested PPARγ activators related to skin pathophysiology. Thiazolidinedione (TZD).

Figure 1

PPARs signaling and functions. (A) Schematic representation of the ligand-dependent PPARs activation. The ligand nature leads to the recruitment of several co-activators or co-repressors, important in driving the PPAR genomic actions. Cytoplasmic PPARs, by interacting with other transcription factors, such as NF-kB, elicit non-genomic effects by negatively regulating pro-inflammatory gene expression (B) Principal roles exerted by the different PPARs isoforms in skin homeostasis.

Figure 2

Three-dimensional structure and ligand binding pocket aminoacid sequences of three PPAR isoforms. (A) 3D structure of PPARα (1I7G [15]), PPARβ/δ (3TKM [16]), and PPARγ (2F4B [17]). (B) Structure-based sequence alignment of hPPARα (UniProt ID Q07869), hPPARβ/δ (UniProt ID Q03181), and hPPARγ (UniProt ID P37231). For each aligned residue pair, “:” is for conserved substitutions, “.” denotes semi-conserved substitutions, and “*” denotes identical residues. Residues binding ligands are highlighted in yellow.