In mammalian skin, permeability barrier function and desquamation are mediated by intercellular stratum corneum lipids. The metabolic pathways whereby epidermis generates lipid for these stratum corneum functions is not well-understood, however, several inherited skin diseases characterized by abnormal desquamation and associated with discrete lipid metabolic defects provide models for the study of these pathways. Some diseases are characterized by accumulation of very long chain (v.l.c.) n-alkanes, also found in normal skin. These studies are based upon the hypothesis that epidermis synthesizes alkanes from fatty acids or alcohols; that changes in the number or function of peroxisomes, a cellular organelle involved in fatty alcohol and v.l.c. fatty acid metabolism, are involved in n-alkane accumulation in outer epidermis; and that delineation of the underlying defect in neutral lipid storage disease (NLSDI), where triglycerides accumulate in viable cells, but alkanes accumulate in stratum corneum, will further illuminate the origin of epidermal alkanes. The defect in NLSDI is postulated to be an intercellular triacylglycerol lipase that generates diacylglycerols for phospholipid biosynthesis. Evidence for alkane biosynthesis will be sought using radiolabelled v.l.c. fatty acids in cultured human keratinocytes (CHK), rodent epidermis in vivo, and in mutant fibroblasts and products analyzed by radiochemical GLC. The relationship of alkane synthesis to differentiation will be assessed in isolated epidermal layers and in CHK cultured by a variety of methods designed to alter differentiation. Peroxisomes will be quantitated in relation to differentiation by ultrastructural cytochemistry for catalase and by three functional assays for peroxisome specific pathways in both CHK and rodent epidermis. The cause of NLSDI will be probed in three NLSDI fibroblast cell lines using radiolabelled precursors and by measurement of pool size using recombinant diacylglycerol kinase. Delineation of the metabolic defect in NLSDI will contribute to our understanding of glycerolipid metabolism and to the origin of epidermal alkanes. Studies with mutant cells which exhibit defects in v.l.c. fatty acid oxidation will aid in our understanding of the role of peroxisomes in normal epidermal lipid metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR029908-09
Application #
3155725
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1981-07-01
Project End
1992-12-31
Budget Start
1991-01-01
Budget End
1991-12-31
Support Year
9
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Emami, S; Hanley, K P; Esterly, N B et al. (1994) X-linked dominant ichthyosis with peroxisomal deficiency. An ultrastructural and ultracytochemical study of the Conradi-Hunermann syndrome and its murine homologue, the bare patches mouse. Arch Dermatol 130:325-36
Schurer, N Y; Stremmel, W; Grundmann, J U et al. (1994) Evidence for a novel keratinocyte fatty acid uptake mechanism with preference for linoleic acid: comparison of oleic and linoleic acid uptake by cultured human keratinocytes, fibroblasts and a human hepatoma cell line. Biochim Biophys Acta 1211:51-60
Aszterbaum, M; Feingold, K R; Menon, G K et al. (1993) Glucocorticoids accelerate fetal maturation of the epidermal permeability barrier in the rat. J Clin Invest 91:2703-8
Boyce, S T; Williams, M L (1993) Lipid supplemented medium induces lamellar bodies and precursors of barrier lipids in cultured analogues of human skin. J Invest Dermatol 101:180-4
Williams, M L; Aszterbaum, M; Menon, G K et al. (1993) Preservation of permeability barrier ontogenesis in the intrauterine growth-retarded fetal rat. Pediatr Res 33:418-24
Williams, M L (1992) Epidermal lipids and scaling diseases of the skin. Semin Dermatol 11:169-75
Ghadially, R; Williams, M L; Hou, S Y et al. (1992) Membrane structural abnormalities in the stratum corneum of the autosomal recessive ichthyoses. J Invest Dermatol 99:755-63
Williams, M L; Menon, G K; Hanley, K P (1992) HMG-CoA reductase inhibitors perturb fatty acid metabolism and induce peroxisomes in keratinocytes. J Lipid Res 33:193-208
Emami, S; Rizzo, W B; Hanley, K P et al. (1992) Peroxisomal abnormality in fibroblasts from involved skin of CHILD syndrome. Case study and review of peroxisomal disorders in relation to skin disease. Arch Dermatol 128:1213-22
Aszterbaum, M; Menon, G K; Feingold, K R et al. (1992) Ontogeny of the epidermal barrier to water loss in the rat: correlation of function with stratum corneum structure and lipid content. Pediatr Res 31:308-17

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