J. Lipid Res. Avanti Polar Lipids
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Originally published In Press as doi:10.1194/jlr.M700475-JLR200 on January 19, 2008

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Journal of Lipid Research, Vol. 49, 738-745, April 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

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

Menno Hoekstra1, Illiana Meurs, Mieke Koenders, Ruud Out, Reeni B. Hildebrand, J. Kar Kruijt, Miranda Van Eck and Theo J. C. Van Berkel

Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, 2300RA Leiden, The Netherlands

Published, JLR Papers in Press, January 19, 2008.

1 To whom correspondence should be addressed. e-mail: 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 scavenger receptor class B type I (SR-BI)-mediated cholesteryl 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 h) stimulated the plasma level of corticosterone by 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 compared with 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 adrenocorticotropic hormone levels were increased by 5-fold in fasted SR-BI-deficient mice. SR-BI deficiency induced marked changes in the hepatic expression of the glucocorticoid-responsive genes cholesterol 7{alpha}-hydroxylase, HMG-CoA synthase, apolipoprotein A-IV, corticosteroid binding globulin, interleukin-6, and tumor necrosis factor-{alpha}, which coincided with a 42% decreased plasma glucose level under fasting conditions. In conclusion, we show that the absence of adrenal HDL cholesteryl ester uptake in SR-BI-deficient mice impairs the adrenal glucocorticoid-mediated stress response to fasting as a result of adrenal glucocorticoid insufficiency and attenuated liver glucocorticoid receptor signaling, leading to hypoglycemia under fasting conditions.

Supplementary key words scavenger receptor class B type I • high density lipoprotein • hormones






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