Effect of regioisomers of hydroxystearic acids as peroxisomal proliferator‐activated receptor agonists to boost the anti‐ageing potential of retinoids

INTRODUCTION: We report on the in vitro and ex vivo effects of chiral (R)‐10‐hydroxystearic acid (10‐HSA) compared with other mono‐hydroxystearic acid regioisomers and stearic acid (SA) together with its benefit when combined with retinol. METHODS: Following treatment with hydroxystearic acids peroxisomal proliferator‐activated receptor alpha (PPARα) activity was determined in a luciferase reporter gene assay, collagen type I was assessed in primary human dermal fibroblasts by immunohistochemistry, modification of the intracellular fibroblast collagen proteome was studied by mass‐spectrometry‐based proteomics and collagen type III was assessed by immunohistochemistry on human ex vivo skin. RESULTS: 10‐HSA was the most effective PPARα agonist (15.7× induction; p < 0.001), followed by 9‐HSA (10.1× induction) and then 12‐HSA (4.9× induction) with 17‐HSA (1.7× induction) being similar to the effects of stearic acid (1.8× induction). Collagen type I levels were increased in primary human fibroblasts by 2.12× and 1.56× for 10‐HSA and 9‐HSA, respectively, in vitro with the10‐HSA being significant (p < 0.05), whereas 12‐HSA and SA had no statistical effect over the untreated control. 10‐HSA and 12‐HSA modified the intracellular fibroblast collagen proteome slightly with significant increases in collagen alpha‐1 (VI) and alpha‐3 (VI) proteins but only 10‐HSA increased levels of collagen alpha‐2 (V), alpha‐1 (III), alpha‐1 (I) and alpha‐2 (I) (all p < 0.05) with the increases being significantly different between 10‐HSA and 12‐HSA for collagen alpha‐1 (I), collagen‐3 (VI) and collagen alpha‐2 (I) (p < 0.01). Collagen type III in ex vivo skin was increased +47% (p < 0.05) by 0.05% (1.7 mM) retinol, +70% (p < 0.01) by 0.01% (0.33 mM) 10‐HSA and the combination increased levels by +240% (p < 0.01 for either ingredient). CONCLUSION: Chiral (R)‐10‐HSA has been shown to be superior to 9, 12 and 17‐HSA as a PPARα agonist. Moreover, 10‐HSA stimulated collagen synthesis in monolayer fibroblast culture as assessed by proteomics and immunohistochemically. Furthermore, we also show the synergistic effects of 10‐HSA with retinol on collagen III synthesis in skin explants. These results further highlight the efficacy of 10‐HSA as a cosmetically acceptable PPARα agonist and anti‐ageing ingredient.