title: Skin Metabolite, Farnesyl Pyrophosphate, Regulates Epidermal Response to Inflammation, Oxidative Stress, and Migration.
abstract: Skin produces cholesterol and a wide array of sterols and non-sterol mevalonate metabolites, including isoprenoid derivative farnesyl pyrophosphate (FPP). To characterize FPP action in epidermis, we generated transcriptional profiles of primary human keratinocytes treated with zaragozic acid (ZGA), a squalene synthase inhibitor that blocks conversion of FPP to squalene resulting in endogenous accumulation of FPP. The elevated levels of intracellular FPP resulted in regulation of epidermal differentiation and adherens junction signaling, insulin growth factor (IGF) signaling, oxidative stress response and interferon (IFN) signaling. Immunosuppressive properties of FPP were evidenced by STAT-1 downregulation and prominent suppression of its nuclear translocation by IFNγ. Furthermore, FPP profoundly downregulated genes involved in epidermal differentiation of keratinocytes in vitro and in human skin ex vivo. Elevated levels of FPP resulted in induction of cytoprotective transcriptional factor Nrf2 and its target genes. We have previously shown that FPP functions as ligand for the glucocorticoid receptor (GR), one of the major regulator of epidermal homeostasis. Comparative microarray analyses show significant but not complete overlap between FPP and glucocorticoid regulated genes, suggesting that FPP may have wider transcriptional impact. This was further supported by co-transfection and chromatin immunoprecipitation experiments where we show that upon binding to GR, FPP recruits β-catenin and, unlike glucocorticoids, recruits co-repressor GRIP1 to suppress keratin 6 gene. These findings have many clinical implications related to epidermal lipid metabolism, response to glucocorticoid therapy as well as pleiotropic effects of cholesterol lowering therapeutics, statins. J. Cell. Physiol. 231: 2452-2463, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Irena
authors.initials: I
authors.lastname: Pastar
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Olivera
authors.initials: O
authors.lastname: Stojadinovic
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Sawaya
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Rivka C
authors.initials: RC
authors.lastname: Stone
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Linsey E
authors.initials: LE
authors.lastname: Lindley
authors.affiliation: Faculty of Medical Sciences, University of the West Indies, Bridgetown, Barbados.
authors.forename: Nkemcho
authors.initials: N
authors.lastname: Ojeh
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University, Atlanta, Geogria.
authors.forename: Sasa
authors.initials: S
authors.lastname: Vukelic
authors.affiliation: Department of Biochemistry and Molecular Pharmacology and Department of Medicine, New York University School of Medicine, New York City, New York.
authors.forename: Herbert H
authors.initials: HH
authors.lastname: Samuels
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida.|John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Marjana
authors.initials: M
authors.lastname: Tomic-Canic
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004817:Epidermis / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007372:Interferons / Q000378:metabolism; D053553:Keratin-6 / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014233:Tricarboxylic Acids / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002352:Carrier Proteins; C491310:GRIP1 protein, human; D053553:Keratin-6; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009419:Nerve Tissue Proteins; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; D014233:Tricarboxylic Acids; D051176:beta Catenin; C075117:squalestatin 1; D007334:Insulin-Like Growth Factor I; C004808:farnesyl pyrophosphate; D003907:Dexamethasone; D007372:Interferons