Absence of HDL cholesteryl ester uptake in mice via SR-BI impairs an adequate adrenal glucocorticoid-mediated stress response to fasting.
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 ( approximately 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 7alpha-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.
Hoekstra
Menno
M
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, 2300RA Leiden, The Netherlands. hoekstra@lacdr.leidenuniv.nl
Meurs
Illiana
I
Koenders
Mieke
M
Out
Ruud
R
Hildebrand
Reeni B
RB
Kruijt
J Kar
JK
Van Eck
Miranda
M
Van Berkel
Theo J C
TJ
D000311:Adrenal Glands / Q000187:drug effects* / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002788:Cholesterol Esters / Q000494:pharmacology*; D005215:Fasting; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size
D001786:Blood Glucose; D018955:CD36 Antigens; D002788:Cholesterol Esters; D005938:Glucocorticoids; C059714:HDL cholesteryl ester; D008075:Lipoproteins, HDL; D000324:Adrenocorticotropic Hormone