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Journal of Lipid Research, Vol. 46, 2657-2666, December 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

LXR and PPAR activators stimulate cholesterol sulfotransferase type 2 isoform 1b in human keratinocytes

Yan J. Jiang^*, Peggy Kim^*, Peter M. Elias^, and Kenneth R. Feingold^1,*,,**

^* Departments of Medicine, University of California San Francisco, San Francisco, CA 94121
Dermatology, University of California San Francisco, San Francisco, CA 94121
Dermatology Service, Veterans Affairs Medical Center, San Francisco, CA 94121
^** Metabolism Section, Veterans Affairs Medical Center, San Francisco, CA 94121

Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.M500235-JLR200

¹ To whom correspondence should be addressed. e-mail: kfngld{at}itsa.ucsf.edu

Liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) are potent regulators of keratinocyte proliferation, differentiation, and epidermal permeability barrier homeostasis. Cholesterol sulfotransferase type 2B isoform 1b (SULT2B1b) is a key enzyme in the synthesis of cholesterol sulfate (CS), a critical regulator of keratinocyte differentiation and desquamation, as well as a mediator of barrier homeostasis. In this study, we assessed the effect of activators of LXR, PPAR, PPARß/, and PPAR on SULT2B1b gene expression and enzyme activity in cultured human keratinocytes (CHKs). Our results demonstrate that PPAR and LXR activators increase SULT2B1b mRNA levels, with the most dramatic effect (a 26-fold increase) induced by the PPAR activator ciglitazone. Ciglitazone upregulates SULT2B1b mRNA in a dose- and time-dependent manner. Moreover, the stimulation of SULT2B1b gene expression by LXR and PPAR activators occurs in both undifferentiated and differentiated CHKs. The upregulation of SULT2B1b mRNA by ciglitazone appears to occur at a transcriptional level, because the degradation of SULT2B1b is not accelerated by ciglitazone. In addition, cycloheximide almost completely blocks the ciglitazone-induced increase in SULT2B1b mRNA, suggesting that the transcription of SULTB1b mRNA is dependent on new protein synthesis. Finally, LXR and PPAR activators also increased the activity of cholesterol sulfotransferase.

Thus, LXR and PPAR activators regulate the expression of SULT2B1b, the key enzyme in the synthesis of CS, which is a potent regulator of epidermal differentiation and corneocyte desquamation.

Abbreviations: CHK, cultured human keratinocyte; CS, cholesterol sulfate; CSTase, cholesterol sulfotransferase; LXR, liver X receptor; 25-OH, 25-hydroxycholesterol; PPAR, peroxisome proliferator-activated receptor; 22R, 22(R)-hydroxycholesterol; RAR, retinoic acid receptor; RXR, retinoid X receptor; SC, stratum corneum; SULT2B1b, cholesterol sulfotransferase type 2B isoform 1b

Supplementary key words cholesterol sulfate • liver X receptor • peroxisome proliferator-activated receptor //

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