- 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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Moshell, Alan N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northern California Institute Research & Education
San Francisco
United States
Zip Code
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

Showing the most recent 10 out of 74 publications