PPARs and LXR Regulate Epidermal Differentiation

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DESCRIPTION (provided by applicant): The epidermis is faced with the daunting task of generating a permeability barrier that allows survival of mammals in a xeric, terrestrial environment. To accomplish this goal, the epidermis generates the stratum corneum (SC), with its highly hydrophobic, lipid-enriched extracellular matrix, organized into lamellar bilayers between rigid corneocytes. To generate these unique protective structures, keratinocytes must synthesize extensive quantities of cholesterol, fatty acids, and ceramides, delivered in an approximately equimolar ratio to the SC, simultaneous with formation of corneocytes, enriched in proteins that are crosslinked to form the cornified envelope. Despite the critical importance of generating this functional, two-compartment SC, the mechanisms that coordinately regulate the parallel formation of corneocytes and the extracellular lamellar membranes remain largely unknown. It is our hypothesis that NHR liposensors (PPAR-alpha, -beta/ delta, -gamma, and LXR) regulate keratinocyte differentiation by first sensing lipid levels, and then coordinately regulating the expression of structural proteins required for corneocyte formation and enzyme proteins that regulate Cer/ GIcCer synthesis, together leading to formation of a functional SC. We propose to determine: 1) whether activation of PPAR-alpha, -delta, and -gamma, and LXR stimulate Cer/ GIcCer synthesis/ lamellar body formation and corneocyte formation; 2) the molecular mechanisms by which activation of PPARs and LXR stimulate expression of corneocyte proteins; 3) the molecular mechanisms by which activators of PPARs and LXR upregulate Cer/ GIcCer production; and finally, 4) to assess whether lipid and protein production are further co-ordinated, such that fluctuations in FA and/ or Chol synthesis co-ordinately regulate corneocyte protein production; i.e., the integration of lipid and protein syntheses that characterizes epidermal differentiation. Since cornification and formation of epidermal barrier lipids, with subsequent generation of the extracellular lamellae, are late steps in epidermal differentiation, the proposed studies will result in significant new information regarding the coordinate regulation of mature SC generation and epidermal homeostasis.