Topical mevalonic acid stimulates de novo cholesterol synthesis and epidermal permeability barrier homeostasis in aged mice

Extracellular lipids of the stratum corneum, which are composed of choleste rol, fatty acid, and ceramides, are essential for the epidermal permeabilit y barrier function. With damage to the barrier, a decreased capacity for ep idermal lipid biosynthesis in aged epidermis results in an impaired repair response, Mevalonic acid is an intermediate after the rate-limiting step in cholesterol biosynthesis, which is catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A reductase. In the present study, we investigated the effect of topical mevalonic acid on the murine epidermal permeability barrier functio n, comparing it with that of cholesterol, Topical treatment with acetone ca used linear increases in transepidermal water loss, in proportion to the nu mber of treatments more rapidly in aged mice than in young mice. Administra tion of mevalonic acid on aged murine epidermis enhanced its resistance aga inst damage and the recovery rate of barrier function from acute barrier di sruption. In contrast, although cholesterol also had the same effect, it re quired a much higher amount than mevalonic acid. In young mice, neither mev alonic acid nor cholesterol had any effect on resistance against acetone da mage nor the recovery rate from acetone damage. In the skin of mice topical ly administered with mevalonic acid, stimulation of cholesterol synthesis a nd 3-hydroxy-3-methylglutaryl coenzyme A reductase activity were both obser ved, whereas none was seen with stimulation by equimolar cholesterol, These data indicate that a topical application of mevalonic acid enhances barrie r recovery in aged mice, which is accompanied by not only acceleration of c holesterol synthesis from mevalonic acid but also stimulation of the whole cholesterol biosynthesis.