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

• Published in: Journal of lipid research 2008-04, Vol.49 (4), p.738-745
• Main Authors: Hoekstra, Menno, Meurs, Illiana, Koenders, Mieke, Out, Ruud, Hildebrand, Reeni B., Kruijt, J. Kar, Van Eck, Miranda, Van Berkel, Theo J.C.
• Format: Article
• Language: English
• Subjects: Adrenal Glands - drug effects; Adrenal Glands - metabolism; Adrenocorticotropic Hormone - blood; Animals; Blood Glucose - metabolism; CD36 Antigens - genetics; CD36 Antigens - metabolism; Cholesterol Esters - pharmacology; Fasting; Female; Glucocorticoids - metabolism; high density lipoprotein; hormones; Lipid Metabolism; Lipoproteins, HDL - pharmacology; Male; Mice; Mice, Knockout; Organ Size; scavenger receptor class B type I
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M700475-JLR200

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 7α-hydroxylase, HMG-CoA synthase, apolipoprotein A-IV, corticosteroid binding globulin, interleukin-6, and tumor necrosis factor-α, 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.