It may be possible to furnish a needed gene product with keratinocytes genetically altered to produce the required protein. However, investigations have been hampered by low initial expression levels from viral promoters. Vectors utilizing mammalian promoters that are normally functional in epidermis, offer potential advantages since the cellular machinery is already set up to express downstream sequences at high levels. We have developed a vector derived from loricrin, the major component of the cornified cell envelope. As an approach to test this promoter in an in vivo protein delivery system we selectively targeted over-expression of Apolipoprotein E(ApoE) in the epidermis of transgenic mice. A functionally impaired form of ApoE is seen in Type III Hyperlipoproteinemia. This is a disorder characterized by elevated serum lipids, accelerated atherosclerosis and cutaneous xanthoma. ApoE is synthesized in most tissues, including the epidermis, however its role in skin remains unknown. Although previous studies have shown that disruption of the cutaneous permeability barrier results in a rapid increase in epidermal ApoE mRNA levels, ApoE-deficient mice do not exhibit abnormalities in permeability barrier function or stratum corneum structure. At birth transgenic mice expressing the ApoE transgene weighed approximately 40% less than normal littermates and exhibited red, tight shiny skin. By 36 hours fissures developed followed by superficial scaling. Severely affected neonates died within 3 days. Histologically, the stratum corneum showed a 3-fold increase in thickness, while the number of nucleated cells revealed no difference from controls. Electron microscopic studies showed apparently normal lipid lamellar granules in the granular layer and lipid multilamellar structures between corneocytes. However, with ruthenium tetroxide staining a large accumulation of lipid was noted both within and between the nucleated cells of the epidermis. Our study suggests that over-accumulation of ApoE in the epidermis may result in abnormal sequestration of lipids that severely retards desquamation and impairs barrier function. In addition, the utility of the loricrin vector for expressing high levels of targeted protein from the epidermis is substantiated.