REGULATION OF EPIDERMAL LIPID METABOLISM

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DESCRIPTION: (Adapted from the applicant's abstract) - Previous studies have demonstrated that repair of barrier following its disruption; 1) requires epidermal lipid synthesis, 2) is associated with increased LDL receptor and apolipoprotein E level, suggesting that uptake of lipids may also be important, and 3) calcium content of the epidermis is an important regulator of their barrier formation. Three hypotheses will be tested. Hypothesis 1 - That the uptake of lipid by keratinocytes plays an important role in barrier homeostasis and that this uptake is mediated by LDL receptor and facilitated by increased expression of LDL receptor, apo E, and LCAT in the epidermis. This hypothesis will be tested by four specific aims. Specific aim one is to determine the location of the increase in LDL receptors and apo E following barrier disruption, 2) determine whether LDL receptor or apo E deficiency impairs barrier repair using LDL and apo E knockout mice, 3) determine whether LCAT activity is stimulated following barrier disruption, and if inhibition of LCAT activity impairs barrier homeostasis, and 4) determine whether circulating lipoproteins play an important role in providing lipids for barrier homeostasis. The second hypothesis is that disruption of barrier alters the distribution and concentration of calcium in the epidermis, and that changes in calcium concentrations is a signal that causes alterations in epidermal lipid metabolisms, which are essential for barrier homeostasis. This hypothesis will be tested by two specific aims; 1) determine whether changes in calcium content in the epidermis regulate lipid metabolism, and 2) determine if the uptake of calcium into cells affects lipid metabolism. The third hypothesis is that alterations in lipid metabolism induced by barrier disruption are coordinately regulated at the level of gene transcription by sterol regulatory element binding proteins (SREBPs). This will be tested by three specific aims; 1) determine if barrier disruption induces an increase in mRNA levels of proteins that are coordinately regulated by SREBPs, 2) determine if 25-hydroxy cholesterol, which inhibits the formation of active SREBPs, blocks the increase in mRNA levels, and 3) determine if the active form of SREBPs is induced by barrier disruption.