Although lipids account for only 10 percent of the total stratum corneum weight they play a critical role in providing for the cutaneous permeability barrier. Studies have demonstrated that the epidermis is a very active site of de novo lipid synthesis, suggesting that the lipids necessary for barrier function are derived primarily from epidermal lipid synthesis. In support of this the investigators have demonstrated that when the permeability barrier is disturbed there is a marked stimulation of epidermal lipid synthesis. Most importantly, when the defect in permeability barrier is corrected by the application of a water-impermeable membrane, the increase in epidermal lipid synthesis is prevented. This suggests that permeability barrier requirements is a crucial factor that regulates epidermal lipogenesis. Moreover, this increase in epidermal lipid synthesis in response to pertubations in barrier function may be essential in the restoration of stratum corneum lipids and the return of barrier function to normal following topical acetone treatment. If epidermal lipid synthesis is prevented by artifically replacing the barrier, neither stratum corneum lipid content nor barrier function recovers following acetone treatment. These observations have led the investigators to the hypothesis that the lipid components of the cutaneous permeability barrier are derived primarily from local epidermal synthesis and this synthesis is regulated by permeability barrier requirements. In the present proposal the investigators plan to extend these observations and answer the following questions: (1) In which layer of the epidermis is lipid synthesis stimulated in response to disturbances in barrier function? (2) Is epidermal lipid synthesis crucial in restoring stratum corneum lipid content and barrier function following the removal of stratum corneum lipids by acetone treatment? (3) Which specific enzymes in the lipid biosynthetic pathways are stimulated by disturbances in the permeability barrier and by what mechanisms are their activities increased? (4) What is the regulatory signal associated with barrier disruption that stimulates epidermal lipid synthesis?

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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General Medicine A Subcommittee 2 (GMA)
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Lu, Biao; Moser, Arthur H; Shigenaga, Judy K et al. (2006) Type II nuclear hormone receptors, coactivator, and target gene repression in adipose tissue in the acute-phase response. J Lipid Res 47:2179-90
Kazemi, Mahmood R; McDonald, Carol M; Shigenaga, Judy K et al. (2005) Adipocyte fatty acid-binding protein expression and lipid accumulation are increased during activation of murine macrophages by toll-like receptor agonists. Arterioscler Thromb Vasc Biol 25:1220-4
Kim, Min Sun; Shigenaga, Judy K; Moser, Arthur H et al. (2005) Suppression of estrogen-related receptor alpha and medium-chain acyl-coenzyme A dehydrogenase in the acute-phase response. J Lipid Res 46:2282-8
Feingold, Kenneth; Kim, Min Sun; Shigenaga, Judy et al. (2004) Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response. Am J Physiol Endocrinol Metab 286:E201-7
Mao-Qiang, Man; Fowler, Ashley J; Schmuth, Matthias et al. (2004) Peroxisome-proliferator-activated receptor (PPAR)-gamma activation stimulates keratinocyte differentiation. J Invest Dermatol 123:305-12
Schmuth, Matthias; Elias, Peter M; Hanley, Karen et al. (2004) The effect of LXR activators on AP-1 proteins in keratinocytes. J Invest Dermatol 123:41-8
Elias, Peter M; Crumrine, Debra; Rassner, Ulrich et al. (2004) Basis for abnormal desquamation and permeability barrier dysfunction in RXLI. J Invest Dermatol 122:314-9
Kim, Min Sun; Shigenaga, Judy; Moser, Art et al. (2004) Suppression of DHEA sulfotransferase (Sult2A1) during the acute-phase response. Am J Physiol Endocrinol Metab 287:E731-8
Kim, Min Sun; Shigenaga, Judy; Moser, Art et al. (2003) Repression of farnesoid X receptor during the acute phase response. J Biol Chem 278:8988-95
Beigneux, Anne P; Moser, Arthur H; Shigenaga, Judy K et al. (2003) Sick euthyroid syndrome is associated with decreased TR expression and DNA binding in mouse liver. Am J Physiol Endocrinol Metab 284:E228-36

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