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• W2142239045 abstract "The isoprenoids farnesol and juvenile hormone III (JH), metabolites of the cholesterol biosynthetic pathway, have been shown to stimulate fetal epidermal development in rodents. In this study we determined whether this effect might be attributed to a direct induction of keratinocytes differentiation and examined the mechanisms responsible for these effects. Rates of cornified envelope formation, a marker of keratinocyte terminal differentiation, as well as protein and mRNA levels of two proteins required for cornified envelope formation, involucrin (INV) and transglutaminase, increased 2- to 3-fold in normal human keratinocytes (NHK) treated with either farnesol or JH, even at low calcium concentrations (0.03 mm), which otherwise inhibit differentiation. In contrast, neither cholesterol nor mevalonate affected INV or transglutaminase mRNA levels. Effects of farnesol and JH on INV and transglutaminase mRNA levels were additive with high calcium concentrations (1.2 mm) that independently stimulate keratinocyte differentiation. In contrast, keratinocyte DNA synthesis was inhibited by these compounds. Both farnesol and JH stimulated INV and transglutaminase promoter activity, suggesting regulation at the transcriptional level. A series of truncation and deletion experiments revealed a farnesol-responsive region (−2452 to −1880 base pairs (bp)) in the INV gene. This region contained an AP-1 site. A single base pair mutation of the AP-1 site at −2116 to −2110 bp abolished farnesol responsiveness, identical to effects by peroxisome proliferator-activated receptor (PPARα) activators. Farnesoid X-activated receptor mRNA was not detected in NHK, but farnesol treatment increased activities of both a PPAR response element and PPARα mRNA levels in NHK. Furthermore, the increase in PPRE activity by farnesol was dependent upon PPARα in CV-1 cells. Finally, topical applications of farnesol increased mRNA and protein levels of the differentiation-specific genes, profilaggrin and loricrin, determined by immunohistochemistry and in situhybridization, in wild-type but not in PPARα−/− murine epidermis. These findings suggest a novel role for selected isoprenoid cholesterol intermediates in the regulation of differentiation-specific gene transcription and a convergence of PPARα with the cholesterol synthetic pathway. The isoprenoids farnesol and juvenile hormone III (JH), metabolites of the cholesterol biosynthetic pathway, have been shown to stimulate fetal epidermal development in rodents. In this study we determined whether this effect might be attributed to a direct induction of keratinocytes differentiation and examined the mechanisms responsible for these effects. Rates of cornified envelope formation, a marker of keratinocyte terminal differentiation, as well as protein and mRNA levels of two proteins required for cornified envelope formation, involucrin (INV) and transglutaminase, increased 2- to 3-fold in normal human keratinocytes (NHK) treated with either farnesol or JH, even at low calcium concentrations (0.03 mm), which otherwise inhibit differentiation. In contrast, neither cholesterol nor mevalonate affected INV or transglutaminase mRNA levels. Effects of farnesol and JH on INV and transglutaminase mRNA levels were additive with high calcium concentrations (1.2 mm) that independently stimulate keratinocyte differentiation. In contrast, keratinocyte DNA synthesis was inhibited by these compounds. Both farnesol and JH stimulated INV and transglutaminase promoter activity, suggesting regulation at the transcriptional level. A series of truncation and deletion experiments revealed a farnesol-responsive region (−2452 to −1880 base pairs (bp)) in the INV gene. This region contained an AP-1 site. A single base pair mutation of the AP-1 site at −2116 to −2110 bp abolished farnesol responsiveness, identical to effects by peroxisome proliferator-activated receptor (PPARα) activators. Farnesoid X-activated receptor mRNA was not detected in NHK, but farnesol treatment increased activities of both a PPAR response element and PPARα mRNA levels in NHK. Furthermore, the increase in PPRE activity by farnesol was dependent upon PPARα in CV-1 cells. Finally, topical applications of farnesol increased mRNA and protein levels of the differentiation-specific genes, profilaggrin and loricrin, determined by immunohistochemistry and in situhybridization, in wild-type but not in PPARα−/− murine epidermis. These findings suggest a novel role for selected isoprenoid cholesterol intermediates in the regulation of differentiation-specific gene transcription and a convergence of PPARα with the cholesterol synthetic pathway. involucrin normal human keratinocyte peroxisome proliferator-activated receptor α peroxisome proliferator response element juvenile hormone III farnesoid-X-activated receptor cornified envelope activator protein-1 retinoic acid receptor keratinocyte growth medium calcium- and magnesium-free phosphate-buffered saline transglutaminase kilobase(s) base pair(s) reverse transcriptase-polymerase chain reaction digoxigenin sterol regulatory element binding protein 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (pirinixic acid) Mammalian epidermis is comprised of stratifying, progressively differentiating keratinocytes, with the cells of each strata displaying a gene expression pattern that reflects the extent of their differentiation (reviewed in Ref. 1.Fuchs E. J. Cell Biol. 1990; 111: 2807-2814Crossref PubMed Scopus (586) Google Scholar). Although proliferative cells in the basal layer express keratin genes, such as K5 andK14, suprabasal cells sequentially express K1 andK10 (2.Fuchs E. Green H. Cell. 1980; 19: 1033-1042Abstract Full Text PDF PubMed Scopus (806) Google Scholar, 3.Roop D.R. Huitfeldt H. Kilkenny A. Yuspa S.H. Differentiation. 1987; 35: 143-150Crossref PubMed Scopus (152) Google Scholar, 4.Ming M.E. Daryanani H.A. Roberts L.P. Baden H.P. Kvedar J.C. J. Invest. Dermatol. 1994; 103: 780-784Abstract Full Text PDF PubMed Scopus (49) Google Scholar), involucrin (INV)1 (5.Robinson N.A. LaCelle P.T. Eckert R.L. J. Invest. Dermatol. 1996; 107: 101-107Abstract Full Text PDF PubMed Scopus (58) Google Scholar, 6.Steinert P.M. Marekov L.N. J. Biol. Chem. 1997; 272: 2021-2030Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar), the calcium-dependent membrane-bound cross-linking enzyme transglutaminase (TG'ase), the intermediate filament-associated protein profilaggrin, loricrin, and other structural protein constituents of the cornified envelope (CE) (7.Thacher S.M. Rice R.H. J. Invest. Dermatol. 1985; 92: 578-584Google Scholar, 8.Steinert P.M. Marekov L.N. J. Biol. Chem. 1995; 270: 17702-17711Abstract Full Text Full Text PDF PubMed Scopus (480) Google Scholar). Many of the genes expressed in these suprabasal layers are necessary for the formation of the CE, the specialized external envelope of the terminally differentiated corneocyte, which confers rigidity and mechanical resistance (9.Reichert U. Michel S. Schmidt R. Darmon M. Blumenberg M. Molecular Biology of the Skin. Academic Press, San Diego1993: 107-150Google Scholar). Corneocytes, the critical structural components of the stratum corneum, together with extracellular lipids, provide the outermost epidermal layer with a barrier to systemic water loss, necessary for life in a terrestrial environment (10.Downing D.T. J. Lipid Res. 1992; 33: 301-313Abstract Full Text PDF PubMed Google Scholar, 11.Elias P.M. Menon G.K. Adv. Lipid Res. 1991; 24: 1-26Crossref PubMed Google Scholar).Increased extracellular calcium, resulting in elevated intracellular calcium, is perhaps the best known signal for the induction of normal human keratinocyte (NHK) differentiation (12.Hennings H. Kruszewski F.H. Yuspa S.H. Tucker R.W. Carcinogenesis. 1989; 4: 777-780Crossref Scopus (117) Google Scholar, 13.Yuspa S.H. Kilkenny A.E. Steinert P.M. Roop D.R. J. Cell. Biol. 1989; 109: 1207-1217Crossref PubMed Scopus (511) Google Scholar). Other extra- and intracellular signals by which NHK differentiation is controlled are not yet fully understood. Numerous studies suggest an important role for RXR-heterodimerizing nuclear hormone receptors in the regulation of epidermal differentiation. The most intensely studied members of this group are retinoic acid receptor (RAR) isoforms. For example, overexpression of a truncated inactive RARα during fetal development results in aberrant epidermal development (14.Imakado S. Bickenbach J.R. Bundman D. Rothnagel J.A. Attar P.S. Wang X.-J. Walczak V.R. Wisniewski S. Pote J. Gordon J.S. Heyman R.A. Evans R.M. Roop D.R. Genes Dev. 1995; 9: 317-329Crossref PubMed Scopus (127) Google Scholar, 15.Saitou M. Sugal S. Tanaka T. Shimouchi K. Fuchs E. Narumiya S. Kakizuka A. Nature. 1995; 374: 159-162Crossref PubMed Scopus (159) Google Scholar), and both systemic and topical RAR ligands modulate epidermal growth and differentiation (16.Kang S. Li X.-Y. Voorhees J.J. J. Invest. Dermatol. Symp. Proc. 1996; 1: 15-21Crossref PubMed Google Scholar, 17.Eichner R. Gendimenico G.J. Kahn M. Mallon J.P. Capetola R.J. Mezick J.A. Br. J. Dermatol. 1996; 135: 687-695Crossref PubMed Scopus (26) Google Scholar, 18.Fisher G.J. Voorhees J.J. FASEB J. 1996; 10: 1002-1013Crossref PubMed Scopus (348) Google Scholar). Ligands of the vitamin D receptor also exert profound, but often opposing, effects from RAR ligands (16.Kang S. Li X.-Y. Voorhees J.J. J. Invest. Dermatol. Symp. Proc. 1996; 1: 15-21Crossref PubMed Google Scholar, 19.Itin P.H. Pittelkow M.R. Kumar R. Endocrinology. 1994; 135: 1793-1798Crossref PubMed Scopus (46) Google Scholar, 20.Bikle D.D. Pillai S. Endocr. Rev. 1993; 14: 3-19PubMed Google Scholar). Additionally, we have shown that ligands and activators of other RXR-interacting receptors, thyroid hormone receptor, peroxisome proliferator-activated receptor (PPARα), and LXR, accelerate both epidermal maturation and the formation of a competent barrier in rodents (21.Hanley K. Jiang Y. Crumrine D. Bass N.M. Appel R. Elias P.M. Williams M.L. Feingold K.R. J. Clin. Invest. 1997; 100: 705-712Crossref PubMed Scopus (141) Google Scholar, 22.Kömüves L.G. Hanley K. Jiang Y. Elias P.M. Williams M.L. Feingold K.R. J. Invest. Dermatol. 1998; 111: 429-433Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 23.Hanley K. Komuves L.G. Bass N.M. He S.S. Jiang Y. Crumrine D. Appel R. Friedman M. Bettencourt J. Min K. Elias P.M. Williams M.L. Feingold K.R. J. Invest. Dermatol. 1999; 113: 788-795Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Furthermore, in normal human keratinocytes, activators of PPARα and LXR, like vitamin D receptor ligands, stimulate differentiation and inhibit proliferation (24.Hanley K. Jiang Y. He S.S. Friedman M. Elias P.M. Bikle D.D. Williams M.L. Feingold K.R. J. Invest. Dermatol. 1998; 110: 368-375Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 25.Hanley K. Ng D.C. He S.S. Lau P. Min K. Elias P.M. Bikle D.D. Mangelsdorf D.J. Williams M.L. Feingold K.R. J. Invest. Dermatol. 1999; 113: 788-795Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar).The farnesoid X-activated receptor (FXR) is another member of the RXR-interacting family. FXR, and its murine homolog RIP14, have been demonstrated in several tissues that are active in sterologenesis such as liver, gut, adrenal gland, and kidney (26.Forman B.M. Goode E. Chen J. Oro A.E. Bradley D.J. Perlmann T. Noonan D.J. Burka L.T. McMorris T. Lamph W.W. Evans R.M. Weinberger C. Cell. 1995; 81: 687-693Abstract Full Text PDF PubMed Scopus (951) Google Scholar). In early studies, farnesol, an isoprenoid in the mevalonate pathway, and the farnesoid metabolite, juvenile hormone III (JH), which regulates metamorphosis in insects (26.Forman B.M. Goode E. Chen J. Oro A.E. Bradley D.J. Perlmann T. Noonan D.J. Burka L.T. McMorris T. Lamph W.W. Evans R.M. Weinberger C. Cell. 1995; 81: 687-693Abstract Full Text PDF PubMed Scopus (951) Google Scholar), were described as activators of FXR·RXR complexes (26.Forman B.M. Goode E. Chen J. Oro A.E. Bradley D.J. Perlmann T. Noonan D.J. Burka L.T. McMorris T. Lamph W.W. Evans R.M. Weinberger C. Cell. 1995; 81: 687-693Abstract Full Text PDF PubMed Scopus (951) Google Scholar). Recently, bile acids have been identified as physiologic ligands for FXR in tissues that express a bile acid transporter such as liver and intestine (27.Wang H. Chen J. Hollister K. Sowers L.C. Forman B.M. Mol. Cell. 1999; 3: 543-553Abstract Full Text Full Text PDF PubMed Scopus (1252) Google Scholar, 28.Parks D.J. Blanchard S.G. Bledsoe R.K. Chandra G. Consler T.G. Kliewer S.A. Stimmel J.B. Willson T.M. Zavacki A.-M. Moore D.D. Lehmann J.M. Science. 1999; 284: 1365-1368Crossref PubMed Scopus (1797) Google Scholar, 29.Makishima H. Okamoto A.Y. Repa J.J. Tu H. Learned R.M. Luk A. Hull M.V. Lustig K.D. Mangelsdorf D.J. Shan B. Science. 1999; 284: 1362-1365Crossref PubMed Scopus (2103) Google Scholar). In liver, activation of FXR inhibits diversion of cholesterol toward bile acid synthesis by decreasing the expression of cholesterol 7α-hydroxylase (27.Wang H. Chen J. Hollister K. Sowers L.C. Forman B.M. Mol. Cell. 1999; 3: 543-553Abstract Full Text Full Text PDF PubMed Scopus (1252) Google Scholar, 28.Parks D.J. Blanchard S.G. Bledsoe R.K. Chandra G. Consler T.G. Kliewer S.A. Stimmel J.B. Willson T.M. Zavacki A.-M. Moore D.D. Lehmann J.M. Science. 1999; 284: 1365-1368Crossref PubMed Scopus (1797) Google Scholar, 29.Makishima H. Okamoto A.Y. Repa J.J. Tu H. Learned R.M. Luk A. Hull M.V. Lustig K.D. Mangelsdorf D.J. Shan B. Science. 1999; 284: 1362-1365Crossref PubMed Scopus (2103) Google Scholar).Previous studies have shown that epidermis is one of the most active sites of steroidogenesis in mammals (30.Feingold K.R. The regulation and role of epidermal lipid synthesis..Adv. Lipid Res. 1991; 24: 57-82Crossref PubMed Google Scholar). Based upon those early observations, we assessed whether farnesol and JH might regulate growth and differentiation. We showed recently that both of these isoprenoids accelerate epidermal development in fetal rats (21.Hanley K. Jiang Y. Crumrine D. Bass N.M. Appel R. Elias P.M. Williams M.L. Feingold K.R. J. Clin. Invest. 1997; 100: 705-712Crossref PubMed Scopus (141) Google Scholar, 23.Hanley K. Komuves L.G. Bass N.M. He S.S. Jiang Y. Crumrine D. Appel R. Friedman M. Bettencourt J. Min K. Elias P.M. Williams M.L. Feingold K.R. J. Invest. Dermatol. 1999; 113: 788-795Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). In the present study we explore the mechanisms responsible for these effects. We show here that farnesol directly stimulates differentiation in NHK as well as in adult murine epidermis. Furthermore, these effects are not mediated by FXR, but rather by PPARα, suggesting that the regulation of keratinocyte differentiation by isoprenoid sterol intermediates is dependent upon PPARα activation.DISCUSSIONRecent studies have revealed that an increasing number of endogenous lipid metabolites, such as lipid-soluble vitamins, fatty acids, and oxysterols, share properties of classic hormones;i.e. they interact directly with nuclear hormone receptors to regulate transcription. Farnesol is a 15-carbon isoprenoid derived from farnesylpyrophosphate, a key intermediate in the cholesterol biosynthetic pathway. The ability of farnesol to accelerate the development of the fetal epidermal permeability barrier led us to ask whether farnesol directly affects differentiation and proliferation in epidermal keratinocytes. Our previous work has shown that fatty acids and oxysterols, activators of the nuclear hormone receptors PPARα and LXR, respectively, stimulate epidermal barrier ontogenesis and keratinocyte differentiation (24.Hanley K. Jiang Y. He S.S. Friedman M. Elias P.M. Bikle D.D. Williams M.L. Feingold K.R. J. Invest. Dermatol. 1998; 110: 368-375Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 25.Hanley K. Ng D.C. He S.S. Lau P. Min K. Elias P.M. Bikle D.D. Mangelsdorf D.J. Williams M.L. Feingold K.R. J. Invest. Dermatol. 1999; 113: 788-795Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). Taken together, these observations suggest that the epidermis, with its high rate of fatty acid and cholesterol synthesis, generates endogenous metabolites that locally regulate keratinocyte growth and differentiation. We explored here whether the sterol intermediates farnesol or JH also regulate NHK growth and differentiation. We show that treatment of NHK with either farnesol or JH results in increased cornified envelope formation and in increased mRNA and protein levels of the differentiation-specific genes INV and transglutaminase, with a parallel inhibition of DNA synthesis.The effects of ligands and activators of nuclear receptors on keratinocyte differentiation in vitro can differ dramatically from those effects that are observed in vivo. For example, all-trans-retinoic acid, the ligand for the retinoic acid receptor, inhibits differentiation in vitro, whereas topical treatment of the intact animal does not suppress differentiation (17.Eichner R. Gendimenico G.J. Kahn M. Mallon J.P. Capetola R.J. Mezick J.A. Br. J. Dermatol. 1996; 135: 687-695Crossref PubMed Scopus (26) Google Scholar, 18.Fisher G.J. Voorhees J.J. FASEB J. 1996; 10: 1002-1013Crossref PubMed Scopus (348) Google Scholar). Conversely, differentiation is stimulatedin vitro but inhibited in vivo by 1,25-dihydroxyvitamin D3, the vitamin D receptor ligand (16.Kang S. Li X.-Y. Voorhees J.J. J. Invest. Dermatol. Symp. Proc. 1996; 1: 15-21Crossref PubMed Google Scholar, 20.Bikle D.D. Pillai S. Endocr. Rev. 1993; 14: 3-19PubMed Google Scholar, 41.Berth-Jones J. Hutchinson P.E. Br. J. Dermatol. 1992; 127: 71-78Crossref PubMed Scopus (47) Google Scholar). Thus, we also examined the effects of farnesol on murine epidermal differentiation in vivo. Farnesol increased the expression of loricrin and filaggrin both at the protein and mRNA level in wild-type mice, indicating that farnesol promotes differentiation in vivo as well as in vitro.Farnesol and JH increase INV and transglutaminase promoter activity, indicating regulation of these genes at the transcriptional level. Our experiments with deletional INV constructs revealed a region of the INV promoter (−2452 bp to −1880 bp) that was responsive to farnesol and JH. Mutation of the AP-1 site within this region abolished farnesol responsiveness, indicating that this AP-1 site is involved in the transcriptional regulation of INV by farnesol. This site also mediates the INV transcriptional response to calcium (33.Ng D.C. Su M.-J. Kim R. Bikle D.D. Front. Biosci. 1996; 1: 16-24Crossref PubMed Google Scholar).2 Our studies suggest, however, that farnesol and JH stimulate differentiation at least in part by a pathway independent of calcium, because in the presence of maximally stimulatory calcium levels, farnesol further increased INV transcription and mRNA levels.Several members of the steroid/nuclear receptor superfamily functionally interact with AP-1 proteins such as c-Jun and c-Fos, which are expressed in differentiated keratinocytes (42.Welter J.F. Eckert R.L. Oncogene. 1995; 11: 2681-2687PubMed Google Scholar). Both positive and negative interactions have been reported, depending on cell type (43, 44 and refs. therein). The cell type specificity is determined in part by the composition of the AP-1 complexes and by interactions with additional transcriptional regulators. Future studies to determine whether nuclear receptors and AP-1 or other transcription factors present in NHK interact to regulate keratinocyte differentiation will contribute to the elucidation of the cascade of events leading to the transcriptional induction of genes such as INV.The farnesol-responsive region on the INV gene (−2452 bp to −1880 bp) which we have localized in the present study is also responsive to PPARα activators (24.Hanley K. Jiang Y. He S.S. Friedman M. Elias P.M. Bikle D.D. Williams M.L. Feingold K.R. J. Invest. Dermatol. 1998; 110: 368-375Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar). Thus we explored the possibility that farnesol-regulated INV transcription occurs via PPARα-mediated pathways. We demonstrate here that farnesol transactivates a PPRE in NHK, and that farnesol and the PPARα-specific activator Wy-14643, when applied together in suboptimal doses, exert additive effects on PPRE activation, whereas no further effects are observed with both agents at maximal concentrations. These results are similar to the combined effects of these agents on fetal epidermal barrier development (21.Hanley K. Jiang Y. Crumrine D. Bass N.M. Appel R. Elias P.M. Williams M.L. Feingold K.R. J. Clin. Invest. 1997; 100: 705-712Crossref PubMed Scopus (141) Google Scholar), which also suggests a common mechanism of action. Additionally, we show that farnesol, like PPARα activators, regulates mRNA levels of PPARα in NHK. Furthermore, in cells that do not contain endogenous PPARs, we demonstrate that PPARα is activated by farnesol, similar to studies by another laboratory (45.O'Brien M.L. Rangwala S.M. Henry K.W. Weinberger C. Crick D.C. Waechter C.J. Feller D.R. Noonan D.J. Carcinogenesis. 1996; 17: 185-190Crossref PubMed Scopus (34) Google Scholar).To clearly delineate the role of PPARα in farnesol-stimulated epidermal differentiation, we examined the effects of topical farnesol on normal murine skin and in mice lacking functional PPARα (PPARα−/−). In previous studies we found that the stimulatory effects of PPARα activators on epidermal differentiation are not observed in PPARα−/− mice, indicating that the effects of these compounds are mediated by PPARα.2 The in vivostudies presented here provide definitive evidence that farnesol also exerts its effects on keratinocyte differentiation via PPARα activation, because farnesol did not stimulate the expression of profilaggrin or loricrin protein or mRNA in PPARα−/− mice. PPARα is a promiscuous receptor that is activated by a wide variety of compounds, including fibrates and fatty acids. Direct binding of farnesol to PPARα has not been observed 3Communication with T. Willson, Glaxo-Wellcome. ; whether PPARα may be activated by a farnesoid metabolite awaits further studies.Fatty acids and cholesterol are major constituents of mammalian cell membranes, and their cellular levels must be regulated so as to provide a balanced supply of these lipids during normal cellular growth. Regulation of lipid synthesis is of further importance in the epidermal keratinocyte, because the generation of large quantities of cholesterol and fatty acid in the proper ratio is critical for the maintenance of the epidermal permeability barrier (46.Mao-Quiang M. Feingold K.R. Elias P.M. Arch. Dermatol. 1993; 129: 728-738Crossref PubMed Scopus (212) Google Scholar). Our results indicate that one mechanism by which this balance may be maintained is through activation of PPARα, which regulates many of the genes involved in fatty acid catabolism, by at least one intermediate in the cholesterol synthetic pathway, farnesol. Another point of transcriptional regulation at which the sterol and fatty acid synthetic pathways converge is through activation of sterol regulatory element binding proteins (SREBPs) by cellular sterols (47.Brown M.S. Goldstein J.L. Cell. 1997; 89: 331-340Abstract Full Text Full Text PDF PubMed Scopus (2941) Google Scholar). SREBPs are membrane-bound transcription factors which, when intracellular sterol levels decrease, are proteolytically cleaved to release the mature form (47.Brown M.S. Goldstein J.L. Cell. 1997; 89: 331-340Abstract Full Text Full Text PDF PubMed Scopus (2941) Google Scholar). This truncated mature form then can enter the nucleus and regulate genes important for cholesterol and fatty acid homeostasis, such as hydroxy-methylglutaryl-coenzyme A synthase and reductase, fatty acid synthase, and acetyl-CoA carboxylase (47.Brown M.S. Goldstein J.L. Cell. 1997; 89: 331-340Abstract Full Text Full Text PDF PubMed Scopus (2941) Google Scholar, 48.Horton J.D. Shimomura I. Brown M.S. Hammer R.E. Goldstein J.L. Shimano H. J. Clin. Invest. 1998; 101: 2331-2339Crossref PubMed Google Scholar, 49.Lopez J.M. Bennett M.K. Sanchez H.B. Rosenfeld J.M. Osborne T.F. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 1049-1053Crossref PubMed Scopus (248) Google Scholar). Thus, cholesterol can regulate fatty acid and cholesterol synthesis in concert via SREBPs, whereas compounds derived from intermediates in the cholesterol synthetic pathway can regulate fatty acid metabolism via PPARα. This provides the cell with multiple mechanisms with which to maintain a balance between two essential membrane lipids and extends the role of isoprenoids beyond protein prenylation and stimulation of apoptosis and inhibition of DNA synthesis (50.Crick D.C. Andres D.A. Waechter C.J. Biochem. Biophys. Res. Commun. 1995; 211: 590-599Crossref PubMed Scopus (63) Google Scholar, 51.Voziyan P.A. Haug J.S. Melnykovych G. Biochem. Biophys. Res. Commun. 1995; 212: 479-486Crossref PubMed Scopus (67) Google Scholar). Finally, previous studies have shown that PPARα activators can ameliorate the epidermal hyperplasia that occurs in essential fatty acid-deficient mice and in murine skin following repeated barrier disruption,2 suggesting that farnesol may be useful as a topical agent for the treatment of various dermatoses characterized by aberrant growth and differentiation.In summary, the results presented here reveal a novel role for the isoprenoid farnesol in PPARα-regulated transcription of differentiation-specific genes and suggest a convergence of the biosynthetic pathways of two of the major lipid species in the skin, fatty acids and cholesterol. Mammalian epidermis is comprised of stratifying, progressively differentiating keratinocytes, with the cells of each strata displaying a gene expression pattern that reflects the extent of their differentiation (reviewed in Ref. 1.Fuchs E. J. Cell Biol. 1990; 111: 2807-2814Crossref PubMed Scopus (586) Google Scholar). Although proliferative cells in the basal layer express keratin genes, such as K5 andK14, suprabasal cells sequentially express K1 andK10 (2.Fuchs E. Green H. Cell. 1980; 19: 1033-1042Abstract Full Text PDF PubMed Scopus (806) Google Scholar, 3.Roop D.R. Huitfeldt H. Kilkenny A. Yuspa S.H. Differentiation. 1987; 35: 143-150Crossref PubMed Scopus (152) Google Scholar, 4.Ming M.E. Daryanani H.A. Roberts L.P. Baden H.P. Kvedar J.C. J. Invest. Dermatol. 1994; 103: 780-784Abstract Full Text PDF PubMed Scopus (49) Google Scholar), involucrin (INV)1 (5.Robinson N.A. LaCelle P.T. Eckert R.L. J. Invest. Dermatol. 1996; 107: 101-107Abstract Full Text PDF PubMed Scopus (58) Google Scholar, 6.Steinert P.M. Marekov L.N. J. Biol. Chem. 1997; 272: 2021-2030Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar), the calcium-dependent membrane-bound cross-linking enzyme transglutaminase (TG'ase), the intermediate filament-associated protein profilaggrin, loricrin, and other structural protein constituents of the cornified envelope (CE) (7.Thacher S.M. Rice R.H. J. Invest. Dermatol. 1985; 92: 578-584Google Scholar, 8.Steinert P.M. Marekov L.N. J. Biol. Chem. 1995; 270: 17702-17711Abstract Full Text Full Text PDF PubMed Scopus (480) Google Scholar). Many of the genes expressed in these suprabasal layers are necessary for the formation of the CE, the specialized external envelope of the terminally differentiated corneocyte, which confers rigidity and mechanical resistance (9.Reichert U. Michel S. Schmidt R. Darmon M. Blumenberg M. Molecular Biology of the Skin. Academic Press, San Diego1993: 107-150Google Scholar). Corneocytes, the critical structural components of the stratum corneum, together with extracellular lipids, provide the outermost epidermal layer with a barrier to systemic water loss, necessary for life in a terrestrial environment (10.Downing D.T. J. Lipid Res. 1992; 33: 301-313Abstract Full Text PDF PubMed Google Scholar, 11.Elias P.M. Menon G.K. Adv. Lipid Res. 1991; 24: 1-26Crossref PubMed Google Scholar). Increased extracellular calcium, resulting in elevated intracellular calcium, is perhaps the best known signal for the induction of normal human keratinocyte (NHK) differentiation (12.Hennings H. Kruszewski F.H. Yuspa S.H. Tucker R.W. Carcinogenesis. 1989; 4: 777-780Crossref Scopus (117) Google Scholar, 13.Yuspa S.H. Kilkenny A.E. Steinert P.M. Roop D.R. J. Cell. Biol. 1989; 109: 1207-1217Crossref PubMed Scopus (511) Google Scholar). Other extra- and intracellular signals by which NHK differentiation is controlled are not yet fully understood. Numerous studies suggest an important role for RXR-heterodimerizing nuclear hormone receptors in the regulation of epidermal differentiation. The most intensely studied members of this group are retinoic acid receptor (RAR) isoforms. For example, overexpression of a truncated inactive RARα during fetal development results in aberrant epidermal development (14.Imakado S. Bickenbach J.R. Bundman D. Rothnagel J.A. Attar P.S. Wang X.-J. Walczak V.R. Wisniewski S. Pote J. Gordon J.S. Heyman R.A. Evans R.M. Roop D.R. Genes Dev. 1995; 9: 317-329Crossref PubMed Scopus (127) Google Scholar, 15.Saitou M. Sugal S. Tanaka T. Shimouchi K. Fuchs E. Narumiya S. Kakizuka A. Nature. 1995; 374: 159-162Crossref PubMed Scopus (159) Google Scholar), and both systemic and topical RAR ligands modulate epidermal growth and differentiation (16.Kang S. Li X.-Y. Voorhees J.J. J. Invest. Dermatol. Symp. Proc. 1996; 1: 15-21Crossref PubMed Google Scholar, 17.Eichner R. Gendimenico G.J. Kahn M. Mallon J.P. Capetola R.J. Mezick J.A. Br. J. Dermatol. 1996; 135: 687-695Crossref PubMed Scopus (26) Google Scholar, 18.Fisher G.J. Voorhees J.J. FASEB J. 1996; 10: 1002-1013Crossref PubMed Scopus (3" @default.
• W2142239045 created "2016-06-24" @default.
• W2142239045 creator A5003154600 @default.
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• W2142239045 title "Farnesol Stimulates Differentiation in Epidermal Keratinocytes via PPARα" @default.
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