Abstract
Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear hormone receptor involved in the transcriptional regulation of lipid metabolism, fatty acid oxidation, and glucose homeostasis. Its activation stimulates antioxidant enzymes such as catalase, whose expression is decreased in aged human skin. Here we investigated the expression of PPARα in aged and ultraviolet (UV)-irradiated skin, and whether PPARα activation can modulate expressions of matrix metalloproteinase (MMP)-1 and procollagen through catalase regulation. We found that PPARα mRNA level was significantly decreased in intrinsically aged and photoaged human skin as well as in UV-irradiated skin. A PPARα activator, Wy14643, inhibited UV-induced increase of MMP-1 and decrease of procollagen expression and caused marked increase in catalase expression. Furthermore, production of reactive oxygen species (ROS) was suppressed by Wy14643 in UV-irradiated and aged dermal fibroblasts, suggesting that the PPARα activation-induced upregulation of catalase leads to scavenging of ROS produced due to UV irradiation or aging. PPARα knockdown decreased catalase expression and abolished the beneficial effects of Wy14643. Topical application of Wy14643 on hairless mice restored catalase activity and prevented MMP-13 and inflammatory responses in skin. Our findings indicate that PPARα activation triggers catalase expression and ROS scavenging, thereby protecting skin from UV-induced damage and intrinsic aging.
Highlights
Skin aging is thought to occur through two processes: intrinsic aging and photoaging
We observed a significant decrease in PPARα mRNA at 6 h post-UV irradiation, which gradually recovered over time (Fig 1C)
Wy14643 (100 μM) was able to significantly reduce intracellular reactive oxygen species (ROS) level (p
Summary
Skin aging is thought to occur through two processes: intrinsic aging and photoaging. Decreased catalase expression may cause ROS accumulation, and ROS has been shown to upregulate MMPs and downregulate collagen synthesis, resulting in accelerated intrinsic aging and photoaging of the human skin [17, 18]. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to a family of nuclear hormone receptors and consist of three isotypes (PPARα, β/δ, and γ) These PPAR isotypes share high degree of structural homology but differ in their functional roles and tissue expression. We investigated PPARα mRNA expression in intrinsically aged and photoaged skins and investigated whether activation of PPARα by an agonist can prevent UV-induced skin damages in human dermal fibroblasts and hairless mice. Our results demonstrate that ligand-activated PPARα was able to attenuate UV-induced secretion of MMP-1 and prevent UV-induced suppression of procollagen expression through ROS inhibition mediated by catalase induction
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