Accelerated Barrier Repair in Human Skin Explants Induced with a Plant-Derived PPAR-α Activating Complex via Cooperative Interactions

George Majewski,1,2 John Craw,1 Timothy Falla1 1Rodan & Fields, San Francisco, CA, 94105, USA; 2Present Affiliation: Contrast Product Development, Walnut, CA, 91789, USACorrespondence: John CrawRodan & Fields, 60 Spear Street, Suite 600, San Francisco, CA, 94105, USAEmail scraw@rodanandfields.comBackground: Peroxisome proliferator-activated receptors (PPARs) govern epidermal lipid synthesis and metabolism. In skin, PPAR activation has been shown to regulate genes responsible for permeability barrier homeostasis, epidermal differentiation, lipid biosynthesis, and inflammation.Objective: Given the known dermatologic benefits of PPARs, we set out to discover a naturally derived, multi-molecule complex that would be superior to the more commonly formulated conjugated linoleic acids (CLAs). We hypothesized that a complex may be capable of modulating PPAR-α by cooperative or multi-ligand binding interactions to accelerate skin barrier repair.Methods: To achieve this, we assembled a novel PPAR-α agonist complex, referred to as RFV3, from a combination of small molecules routinely used in Ayurvedic medicine and accepted in cosmetic and topical over-the-counter dermatologic products. We tested RFV3’s potential as a PPAR-α agonist by evaluating its transcriptional response, ligand binding affinity to PPAR-α, gene expression profiles and barrier repair properties in human skin explant models.Results: We assembled RFV3 by solubilizing two standardized plant extracts in a suitable solvent and induced a significant transcriptional response in PPAR-α luciferase reporter assay. Furthermore, transcriptome profiling of RFV3-treated epidermal substitutes revealed expressed genes consistent with known targets of PPAR-α, including those involved in epidermal barrier repair. In addition, in silico modeling demonstrated differential co-binding affinities of RFV3 to PPAR-α compared with those of the endogenous ligands (CLAs) and a synthetic PPAR-α agonist. Lastly, delipidated skin explant models confirmed accelerated barrier repair activity with significant increases in ceramides, filaggrin and transglutaminase-1 after treatment.Conclusion: These findings suggest that the RFV3 complex successfully mimics a PPAR-α agonist and induces synthesis of skin barrier lipids and proteins consistent with known PPAR pathways.Keywords: PPAR-α, cooperative binding, epidermal barrier, explants, ceramide