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Topical Mevalonic Acid Stimulates De Novo Cholesterol Synthesis and Epidermal Permeability Barrier Homeostasis in Aged Mice1

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Topical Mevalonic Acid Stimulates De Novo Cholesterol Synthesis and Epidermal Permeability Barrier Homeostasis in Aged Mice1 View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Topical Mevalonic Acid Stimulates De Novo Cholesterol Synthesis and Epidermal Permeability Barrier Homeostasis in Aged Mice1 Akinori Haratake, Kenji Ikenaga,* Norito Katoh,* Hideyo Uchiwa, Shinya Hirano,* and Hirokazu Yasuno* Basic Research Laboratory, Kanebo Ltd, Odawara, Japan; *Department of Dermatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan Extracellular lipids of the stratum corneum,which cholesterol also had the same effect,it required a are composed of cholesterol,fatty acid,and cera- much higher amount than mevalonic acid. In young mides,are essential for the epidermal permeability mice,neither mevalonic acid nor cholesterol had barrier function. With damage to the barrier,a any effect on resistance against acetone damage nor decreased capacity for epidermal lipid biosynthesis in the recovery rate from acetone damage. In the skin aged epidermis results in an impaired repair of mice topically administered with mevalonic acid, response. Mevalonic acid is an intermediate after the stimulation of cholesterol synthesis and 3-hydroxy- rate-limiting step in cholesterol biosynthesis,which 3-methylglutaryl coenzyme A reductase activity is catalyzed by 3-hydroxy-3-methylglutaryl coenzyme were both observed,whereas none was seen with A reductase. In the present study,we investigated stimulation by equimolar cholesterol. These data the effect of topical mevalonic acid on the murine indicate that a topical application of mevalonic acid epidermal permeability barrier function,comparing enhances barrier recovery in aged mice,which is it with that of cholesterol. Topical treatment with accompanied by not only acceleration of cholesterol acetone caused linear increases in transepidermal synthesis from mevalonic acid but also stimulation water loss,in proportion to the number of treat- of the whole cholesterol biosynthesis. Key words: ments more rapidly in aged mice than in young acetone treatment/aging/cholesterol synthesis/damaged mice. Administration of mevalonic acid on aged skin/epidermal permeability barrier/HMG-CoA reductase/ murine epidermis enhanced its resistance against homeostasis/mevalonic acid/ transepidermal water loss. J damage and the recovery rate of barrier function Invest Dermatol 114:247±252, 2000 from acute barrier disruption. In contrast,although ne of the major functions of epidermis is as a Focally decrease numbers of the stratum corneum lamellar permeability barrier against excess body water loss bilayers, with an accompanying decrease in secretion of lamellar and cutaneous permeability. The stratum corneum body content and total intercellular lipids quantity of intercellular Ois the permeability barrier site, and is comprised of lipids have been reported as changes that occur in the epidermal stratum corneum cells and intercellular lipids with a permeability barrier of intrinsically aged skin, whereas the thickness lamellar structure (Elias and Friend, 1975; Elias, 1983). Intercellular of the stratum corneum remains normal and distribution of lipids are mainly composed of cholesterol, ceramides, and free fatty ceramides, cholesterol, and free fatty acids unchanged (Ghadially acids which are biosynthesized in the epidermis (review, Feingold, et al, 1995). After either acetone treatment or tape stripping, the 1991; Jackson et al, 1993). Disruptions of the barrier by treatment barrier recovers more slowly in aged skin than in young skin with organic solvents, detergent, or tape stripping results in an (Ghadially et al, 1995, 1996). In addition, with damage to the increase of transepidermal water loss (TEWL). This barrier barrier, a decreased capacity of aged epidermis for lipid synthesis, in abrogation is followed by increased lipid synthesis in the epidermis particular cholesterol synthesis, results in an impaired repair which is necessary for the synthesis of new lamellar bodies and the response (Ghadially et al, 1996). Several attempts have been secretion of lamellar body lipids, thus leading to the recovery of performed to improve such impaired repair response. Ghadially et al normal barrier functions (review, Feingold, 1991a). (1996) reported that a topical application of cholesterol after barrier abrogation accelerated barrier recovery in aged epidermis. Manuscript received January 5, 1999; revised October 29, 199; accepted Furthermore, a topical application of cholesterol-dominant stratum for publication November 3, 1999. corneum lipid mixture (cholesterol/ceramide/palmitate/linoleate; Reprint requests to: Mr Akinori Haratake, Basic Research Laboratory, 3:1:1:1) after barrier disruption by tape stripping was found to Kanebo Ltd, 3-28 5-chome, Kotobuki-cho, Odawara-shi, Kanagwa, 250- accelerate barrier recovery in chronologically aged murine and 0002, Japan. Abbreviations: HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; human skin (Zettersten et al, 1997). It is considered that topical TEWL, transepidermal water loss. physiologic lipid mixtures in¯uence barrier recovery after transport 1The authors did not submit a completed declaration of con¯ict of to subjacent, nucleated layers, followed by internalization, then an interest form as requested by the JID's ``Information for authors''. apparent transport to the distal Golgi apparatus, incorporation into 0022-202X/00/$15.00 ´ Copyright # 2000 by The Society for Investigative Dermatology, Inc. 247 248 HARATAKE ET AL THE JOURNAL OF INVESTIGATIVE DERMATOLOGY nascent lamellar bodies, and secretion of the lamellar body into the Barrier integrity and barrier recovery The samples (vehicle, stratum corneum (Mao-Qiang et al, 1995; Madison et al, 1996). cholesterol, or mevalonic acid, 50 ml of 7.68 mM sample) were applied on the dorsal surface (2.5 cm2 area) of mice for 5 d (once a day) before the Thus, de novo biosynthesis of lipids is an important mechanism for acetone treatments or tape stripping. For assessment of barrier integrity, the acceleration of barrier recovery by topical administration with a TEWL was measured immediately after each ®ve acetone treatments. physiologic lipid. Barrier integrity (strength against arti®cial damage) was re¯ected by the Cholesterol synthesis is required for the permeability barrier. In number of acetone treatments or tape strippings required to attain TEWL the biosynthetic pathway of cholesterol, the conversion of 3- levels of > 0.15 mg per cm2 per min. For assessment of barrier recovery hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonic from arti®cial damage, mice received acetone treatment or tape stripping to acid is an early and rate-limiting step in the formation of attain TEWL levels of 0.15 mg per cm2 per min after the sample applications for 5 d, then had the sample applied once again. TEWL was endogenous cholesterol (Lea and McTavish, 1997). Lovastatin, an measured before, 2, 4, 24, and 48 h after barrier disruption by arti®cial inhibitor of HMG-CoA reductase, interfered with barrier recovery damage. Data are expressed as the percentage of barrier recovery (0 h = 0% after acute perturbation (Feingold et al, 1990, 1991b). Barrier recovery, normal = 100%, mean 6 SEM). recovery, however, was restored to normal when lovastatin-treated young mice were simultaneously treated with mevalonate Cholesterol biosynthesis in organ cultured epidermis Full-thickness (Feingold et al, 1990). Mevalonate is also an intermediate skin samples were obtained from aged mice at 3 h after topical application compound of other synthetic pathways. It was previously shown of the samples (vehicle, cholesterol, or mevalonic acid, 50 ml of sample that parts of applied mevalonate are incorporated in the cholesterol applied to a 2.5 cm2 area). Subcutaneous fat was scraped off full-thickness synthetic pathway, and applied cholesterol and mevalonate are murine skin. Cholesterol biosynthesis in the epidermis was assessed by measuring the incorporation of [1-14C]acetic acid into tissue in a skin organ similarly incorporated into keratinocytes, then recovery of the culture. Brie¯y, the organ culture (2 cm2 skin pieces) were incubated in barrier occurs (Feingold et al, 1990). Therefore, it was expected that phosphate-buffered saline (pH 7.4) including 10 mmol EDTA, acetic acid an administration of mevalonic acid would be able to accelerate sodium salt, and [1-14C]acetic acid (0.74 MBq) for 2 h at 37°C, and the de novo cholesterol synthesis more than cholesterol treatment in epidermis was separated by gently scraping with a scalpel blade. aged epidermis, resulting in an improvement of the epidermal Incorporation activity of [14C] into cholesterol was measured according permeability barrier homeostasis. to the method of Feingold et al (1986). Cholesterol syntheses are expressed The purpose of this study was to investigate the effect of topical as dpm per hour per gram of epidermis (mean 6 SEM). mevalonic acid on the murine epidermal permeability barrier function, comparing it with topical cholesterol. We found that: (i) HMG-CoA reductase activity assay The samples (vehicle, cholesterol, or mevalonic acid, 50 ml) were applied on the dorsal surface (2.5 cm2 area) the effect of topical cholesterol in aged mice was con®rmed, and (ii) of mice once a day for 5 d. For measurement of HMG-CoA reductase a topical application of mevalonic acid enhances barrier recovery in activity, skin samples were incubated in phosphate-buffered saline (pH 7.4) aged mice, which is accompanied by not only an acceleration
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