出版社：American Society for Biochemistry and Molecular Biology
摘要：Keratinocytes require abundant cholesterol for cutaneous permeabilitybarrier function; hence, the regulation of cholesterol homeostasisis of great importance. ABCA1 is a membrane transporter responsiblefor cholesterol efflux and plays a pivotal role in regulatingcellular cholesterol levels. We demonstrate that ABCA1 is expressedin cultured human keratinocytes (CHKs) and murine epidermis.Liver X receptor (LXR) activation markedly stimulates ABCA1mRNA and protein levels in CHKs and mouse epidermis. In additionto LXR, activators of peroxisome proliferator-activated receptor(PPAR), PPARß/, and retinoid X receptor (RXR), butneither PPAR nor retinoic acid receptor, also increase ABCA1expression in CHKs. Increases in cholesterol supply inducedby LDL or mevalonate stimulate ABCA1 expression, whereas inhibitingcholesterol synthesis with statins or cholesterol sulfate decreasesABCA1 expression in CHKs. After acute permeability barrier disruptionby either tape-stripping or acetone treatment, ABCA1 expressiondeclines, and this attenuates cellular cholesterol efflux, makingmore cholesterol available for regeneration of the barrier.In addition, during fetal epidermal development, ABCA1 expressiondecreases at days 18–22 of gestation (term = 22 days),leaving more cholesterol available during the critical periodof barrier formation. Together, our results show that ABCA1is expressed in keratinocytes, where it is negatively regulatedby a decrease in cellular cholesterol levels or altered permeabilitybarrier requirements and positively regulated by activatorsof LXR, PPARs, and RXR or increases in cellular cholesterollevels.Supplementary key words ATP binding cassette transporter 1 • liver X receptor • peroxisome proliferator-activated receptor • peroxisome proliferator-activated receptor • peroxisome proliferator-activated receptor • cultured human keratinocyte
Abbreviations: ATRA, all-trans-retinoic acid; 8-Br-cAMP, 8-bromoadenosine-3',5'-cyclic monophosphate; CHK, cultured human keratinocyte; 9-cis-RA, 9-cis-retinoic acid; CS, cholesterol sulfate; LXR, liver X receptor; 25(OH), 25-hydroxycholesterol; PPAR, peroxisome proliferator-activated receptor; 22R, 22(R)-hydroxycholesterol; RXR, retinoid X receptor; TO, TO901317
, PPARß/
, and retinoid X receptor (RXR), but neither PPAR
nor retinoic acid receptor, also increase ABCA1 expression in CHKs. Increases in cholesterol supply induced by LDL or mevalonate stimulate ABCA1 expression, whereas inhibiting cholesterol synthesis with statins or cholesterol sulfate decreases ABCA1 expression in CHKs. After acute permeability barrier disruption by either tape-stripping or acetone treatment, ABCA1 expression declines, and this attenuates cellular cholesterol efflux, making more cholesterol available for regeneration of the barrier. In addition, during fetal epidermal development, ABCA1 expression decreases at days 18–22 of gestation (term = 22 days), 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.
Supplementary key words ATP binding cassette transporter 1 • liver X receptor • peroxisome proliferator-activated receptor 
