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Papers In Press, published online ahead of print July 6, 2006
J. Lipid Res., doi:10.1194/jlr.M600163-JLR200
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Metabolism Section, 111F, University of California San Francisco, San Francisco, CA 94121
Corresponding Author: yan.jiang{at}med.va.gov
Keratinocytes require abundant cholesterol for cutaneous permeability barrier function; hence, regulation of cholesterol homeostasis is of great importance. ABCA1 is a membrane transporter responsible for cholesterol efflux and plays a pivotal role in regulating cellular cholesterol levels. We demonstrate that ABCA1 is expressed in cultured human keratinocytes (CHK) and murine epidermis. LXR activation markedly stimulates ABCA1 mRNA and protein levels in CHK and mouse epidermis. In addition to LXR, activators of PPAR-alpha, PPAR-ß/delta and RXR, but neither PPAR-gamma nor RAR, also increase ABCA1 expression in CHK. Increases in cholesterol supply induced by LDL or mevalonate stimulate ABCA1 expression, while inhibiting cholesterol synthesis with statins or cholesterol sulfate decrease ABCA1 expression in CHK. Following acute permeability barrier disruption by either tape-stripping or acetone treatment, ABCA1 expression declines, and this attenuates cellular cholesterol efflux, thereby making more cholesterol available for regeneration of the barrier. In addition, during fetal epidermal development, ABCA1 expression decreased at days 18-22 of gestation, leaving more cholesterol available during the critical period of barrier formation. Together, our results show that ABCA1 is expressed in keratinocytes where it is negatively regulated by a decrease in cellular cholesterol levels or altered permeability barrier requirements and positively regulated by activators of LXR, PPARs and RXR or increases in cellular cholesterol levels.
Revised on June 20, 2006
Accepted on July 5, 2006
Regulation of ABCA1 expression in human keratinocytes and murine epidermis
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