Submitted on August 17, 2006
Revised on October 12, 2006
Accepted on October 27, 2006
Inter-relationship between inflammation and cholesterol accumulation in LDLr-/-, apoA-I-/- mice: connection between cholesterol homeostasis and self-tolerance?
Manal Zabalawi, Manish Bharadwaj, Heather Horton, Mark Cline, Mark Willingham, Michael J. Thomas, and Mary G. Sorci-Thomas
Dept of Pathology, Wake Forest University Medical Center, Winston-Salem, NC 27157
Corresponding Author: msthomas{at}wfubmc.edu
Diet-fed LDLr-/-, apoA-I-/- mice accumulate a 10-fold greater mass of cholesterol in their skin despite a 1.5-2-fold lower plasma cholesterol concentration when compared to diet-fed LDLr-/- mice. The accumulation of cholesterol predominately in the skin has been shown to occur in a growing number of other hypercholesterolemic double knockout mouse models sharing in common 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 wk of diet, LDLr-/-, apoA-I-/- mice showed a significant increase in skin cholesterol mass compared to LDLr-/- mice. In addition, after 4 wk on the diet, cholesterol accumulation in the skin was also found to be associated with macrophage infiltration and accompanied by an increase in TNFa, COX-2 and langerin mRNA, which was not seen in the liver. Overall, these data suggest that as early as 4 wk 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 for investigating the role apoA-I plays in maintaining cholesterol homeostasis and its relationship to inflammation.
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