Critical roles of the nuclear receptor PPARβ (peroxisome-proliferator-activated receptor β) in skin wound healing

The PPARs (peroxisome-proliferator-activated receptors) α, β/δ and γ belong to the nuclear hormone receptor superfamily. While all three receptors are undetectable in adult mouse interfollicular epidermis, PPARβ expression and activity is strongly re-activated by inflammatory stimuli during epidermal injury. The pro-inflammatory cytokine TNFα (tumour necrosis factor α) stimulates transcription of the PPARβ gene via an activator protein-1 site in its promoter and it also triggers the production of PPARβ ligands in keratinocytes. This increase of PPARβ activity in these cells up-regulates the expression of integrin-linked kinase and 3-phosphoinositide-dependent kinase-1, which phosphorylates protein kinase B-α (Akt1). The resulting increase in Akt1 activity suppresses apoptosis and ensures the presence of a sufficient number of viable keratinocytes at the wound margin for re-epithelialization. Together, these observations reveal that PPARβ takes on multiple roles and contributes favourably to the process of wound closure. Introduction The PPAR (peroxisome-proliferator-activated receptor) subfamily includes three isotypes (α, β/δ and γ ; NR1C1, NR1C2 and NR1C3, respectively) that play a major role in the sensing and metabolism of biologically active lipids. As sensor receptors, PPARs are activated by a wide range of fatty acids, oxidized fatty acids metabolites from the lipoxygenase and cyclo-oxygenase pathways, and selective synthetic compounds e.g. hypolipidaemic fibrates and insulinsensitizing thiazolidinediones [1]. The biological roles of PPARα and γ have been well-documented and thus will not be reiterated herein [2,3]. The canonical pathway by which PPARs regulate gene transcription involves their initial activation by ligand binding and subsequent heterodimerization with the RXR (retinoid X receptor). The PPAR–RXR heterodimer binds to the DNA response element (called PPAR response element or PPRE) that resides in the promoter or intronic regions of target genes (Figure 1). Concomitantly, nuclear receptor co-activators interact with PPAR–RXR and mediate transactivation, in part by contributing to the recruitment and stabilization of active transcriptional complexes. Similar to other nuclear receptors, phosphorylation of PPARs can also modulate their transactivation potential [4]. Interestingly, PPARβ actions can also result in gene repression. Unliganded PPARβ was demonstrated to be associated with corepressors, such as SMRT (silencing mediator for retinoid