J. Lipid Res.
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A more recent version of this article appeared on April 1, 2008

Papers In Press, published online ahead of print January 19, 2008
J. Lipid Res., doi:10.1194/jlr.M700475-JLR200
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Submitted on October 19, 2007
Revised on January 18, 2008
Accepted on January 19, 2008

Absence of HDL cholesterol ester uptake in mice via SR-BI impairs an adequate adrenal glucocorticoid-mediated stress response to fasting

Menno Hoekstra, Illiana Meurs, Mieke Koenders, Ruud Out, Reeni B. Hildebrand, J. Kar Kruijt, Miranda Van Eck, and Theo J.C. Van Berkel

Division of Biopharmaceutics, Gorlaeus Laboratories, Leiden/Amsterdam Center for Drug Research, Leiden, Zuid-Holland 2300 RA

Corresponding Author: hoekstra{at}lacdr.leidenuniv.nl

Receptor-mediated cholesterol uptake has been suggested to play a role in maintaining the adrenal intracellular free cholesterol pool and the ability to produce hormones. Therefore, in the current study, we evaluated the importance of SR-BI-mediated cholesterol ester uptake from HDL for adrenal glucocorticoid hormone synthesis in vivo. No difference was observed in the plasma level of corticosterone between SR-BI deficient and wild-type mice under ad libitum feeding conditions. Overnight fasting (~16 hours) stimulated the plasma level of corticosterone 2-fold in wild-type mice. In contrast, no effect of fasting on plasma corticosterone levels was observed in SR-BI deficient mice, leading to a 44% lower plasma corticosterone level as compared to their wild-type littermate controls. In parallel, an almost complete depletion of lipid stores in the adrenal cortex of fasted SR-BI deficient mice was observed. Plasma ACTH levels were 5-fold increased in fasted SR-BI deficient mice. SR-BI deficiency induced marked changes in the hepatic expression of the glucocorticoid-responsive genes CYP7A1, HMGCS, ApoA-IV, CBG, IL-6, and TNFalpha, which coincided with a 42% lowered plasma glucose levels under fasting conditions. In conclusion, we show that the absence of adrenal HDL cholesterol ester uptake in SR-BI deficient mice impairs the adrenal glucocorticoid-mediated stress response to fasting due to adrenal glucocorticoid insufficiency, and attenuated liver glucocorticoid receptor signalling leading to hypoglycaemia under fasting conditions.


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