Cholesterol sulfate and wax monoesters are abundant lipids in the skin whose biological roles and biosynthetic pathways remain largely undefined. Cholesterol sulfate is synthesized by the SULT2B1 sulfotransferase enzyme and is postulated to be an essential regulatory and structural component in the formation of the epidermal lipid barrier. The biosynthetic pathway that produces wax monoesters has not been defined in mammals but by analogy to plants and lower organisms is thought to involve the sequential actions of two enzymes, a fatty acyl coenzyme A (CoA) reductase and a wax ester synthase. Our initial goal will be to characterize the phenotype of mice that lack cholesterol sulfotransferase. Targeted gene disruption has produced SULT2B1 knockout mice that will be studied with respect to skin barrier function, lipid metabolism and reproduction. The second goal is to determine the role of cholesterol sulfotransferase in vitro by characterizing Chinese hamster ovary cell lines that over-express SULT2B1 and primary mouse embryo fibroblasts and keratinocytes that lack this enzyme. Sterol metabolism, gene regulation, and differentiation of these cells will be analyzed. Our third goal is to define the mammalian wax monoester biosynthetic pathway. Bioinformatics and expression cloning have produced mouse cDNAs encoding two fatty acyl CoA reductases and a wax synthase. The biochemical properties, subcellular Iocalizations, and tissue distributions of these enzymes will be determined. The final objective is to produce mice that are deficient in the wax synthase enzyme. The resulting knockout animals will be used to determine the function of wax monoesters in the skin, eye, and immune system. The proposed studies will provide new insight into the enzymes of skin lipid metabolism and the roles that unique lipids play in preventing infection, dehydration, and abrasion. The research is relevant to skin disease, dry eye syndrome, and cholesterol metabolism.
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