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Papers In Press, published online ahead of print January 1, 2007
J. Lipid Res., doi:10.1194/jlr.M600370-JLR200

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Journal of Lipid Research, Vol. 48, 52-65, January 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Inflammation and skin cholesterol in LDLr^–/–, apoA-I^–/– mice: link between cholesterol homeostasis and self-tolerance?

Manal Zabalawi^*,, Manish Bharadwaj^*,, Heather Horton^*,, Mark Cline, Mark Willingham, Michael J. Thomas and Mary G. Sorci-Thomas^1,*,,

^* Lipid Sciences Research Center, Wake Forest University Medical Center, Winston-Salem, NC 27157
Department of Pathology, Wake Forest University Medical Center, Winston-Salem, NC 27157
Department of Biochemistry, Wake Forest University Medical Center, Winston-Salem, NC 27157c

Published, JLR Papers in Press, October 28, 2006.

¹ To whom correspondence should be addressed. e-mail: msthomas{at}wfubmc.edu

Diet-fed low density lipoprotein receptor-deficient/apolipoprotein A-I-deficient (LDLr^–/–, apoA-I^–/–) mice accumulate a 10-fold greater mass of cholesterol in their skin despite a 1.5- to 2-fold lower plasma cholesterol concentration compared with diet-fed LDLr^–/– mice. The accumulation of cholesterol predominantly in the skin has been shown to occur in a growing number of other hypercholesterolemic double knockout mouse models sharing deficits in genes regulating cellular cholesterol homeostasis. Exploring the relationship between cholesterol balance and inflammation, we have examined the time course of cholesterol accumulation in a number of extrahepatic tissues and correlated with the onset of inflammation in diet-fed LDLr^–/–, apoA-I^–/– mice. After 4 weeks of diet, LDLr^–/–, apoA-I^–/– mice showed a significant increase in skin cholesterol mass compared with LDLr^–/– mice. In addition, after 4 weeks on the diet, cholesterol accumulation in the skin was also found to be associated with macrophage infiltration and accompanied by increases in tumor necrosis factor-, cyclooxygenase-2, and langerin mRNA, which were not seen in the liver. Overall, these data suggest that as early as 4 weeks after starting the diet, the accumulation of skin cholesterol and the onset of inflammation occur concurrently. In summary, the use of hypercholesterolemic LDLr^–/–, apoA-I^–/– mice may provide a useful tool to investigate the role that apoA-I plays in maintaining cholesterol homeostasis and its relationship to inflammation.

Supplementary key words apolipoprotein A-I • high density lipoprotein • inflammation • low density lipoprotein receptor-deficient/apolipoprotein A-I-deficient mice • whole body cholesterol • skin • itch

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