Nuclear hormone receptors and epidermal differentiation

Lipophilic compounds are potent regulators of epidermal differentiation and cornification and their actions are mediated by nuclear hormone receptors. Different nuclear hormone receptors exert distinct systemic activity on energy- and lipid-metabolism, indicating that the mechanisms by which these receptors regulate keratinocyte function are not identical and that their functions are not overlapping or redundant. It is likely that there are also important differences in the effects of individual receptors on the epidermis. Thus, the present proposal is designed to dissect the differential effects of several class II nuclear hormone receptors on epidermal differentiation and cornification, including the peroxisome proliferator activated receptors (PPAR), liver X receptors (LXR), pregnane X receptor (PXR), and the constitutive androstane receptor (CAR). In these studies, we will use a variety of receptor specific activators in combination with receptor deficient animal models. Conversely, we will assess epidermal morphology and differentiation in a mouse model of ligand deficiency. Finally, using in vitro-assays, we will explore the mechanistic basis of the epidermal effects of nuclear hormone receptors. The current proposal will provide insight into how the differentiation of the epidermis is coordinated so that the endproduct, the outermost cornified layer of the skin, consisting of lipid lamellar membranes (required for the permeability barrier) and the cornified envelope (required for mechanical strength) are formed simultaneously. This information should clarify the mechanisms by which lipid factors regulate this process. It may also provide the basic science understanding that will allow for the development of compounds that stimulate these nuclear hormone receptors for clinical use in the treatment of skin diseases.

Lipophilic compounds are potent regulators of epidermal differentiation and cornification and their actions are mediated by nuclear hormone receptors. Different nuclear hormone receptors exert distinct systemic activity on energy- and lipid-metabolism, indicating that the mechanisms by which these receptors regulate keratinocyte function are not identical and that their functions are not overlapping or redundant. It is likely that there are also important differences in the effects of individual receptors on the epidermis. Thus, the present proposal is designed to dissect the differential effects of several class II nuclear hormone receptors on epidermal differentiation and cornification, including the peroxisome proliferator activated receptors (PPAR), liver X receptors (LXR), pregnane X receptor (PXR), and the constitutive androstane receptor (CAR). In these studies, we will use a variety of receptor specific activators in combination with receptor deficient animal models. Conversely, we will assess epidermal morphology and differentiation in a mouse model of ligand deficiency. Finally, using in vitro-assays, we will explore the mechanistic basis of the epidermal effects of nuclear hormone receptors. The current proposal will provide insight into how the differentiation of the epidermis is coordinated so that the endproduct, the outermost cornified layer of the skin, consisting of lipid lamellar membranes (required for the permeability barrier) and the cornified envelope (required for mechanical strength) are formed simultaneously. This information should clarify the mechanisms by which lipid factors regulate this process. It may also provide the basic science understanding that will allow for the development of compounds that stimulate these nuclear hormone receptors for clinical use in the treatment of skin diseases.