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Journal of Lipid Research, Vol. 50, 1039-1046, June 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocorticoid production

Menno Hoekstra¹, Dan Ye, Reeni B. Hildebrand, Ying Zhao, Bart Lammers, Miranda Stitzinger, Johan Kuiper, Theo J. C. Van Berkel and Miranda Van Eck

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

This research was supported by Top Institute Pharma (TIPharma project T2-110; M.H. and T.J.C.V.B.), by Grants 2001T41 (M.V.E.), 2006B107 (B.L), and 2008T070 (M.H.) from the Netherlands Heart Foundation, and by VIDI Grant 917.66.301 from the Netherlands Organization for Scientific Research (M.V.E.). M.V.E. is an Established Investigator of the Netherlands Heart Foundation (Grant 2007T056).

Published, JLR Papers in Press, January 28, 2009.

¹ To whom correspondence should be addressed. e-mail: hoekstra{at}lacdr.leidenuniv.nl

Impaired scavenger receptor class B type I (SR-BI)-mediated uptake of HDL-cholesterol esters (HDL-CE) induces adrenal insufficiency in mice. Humans contain an alternative route of HDL-CE clearance, namely through the transfer by cholesteryl ester transfer protein (CETP) to apolipoprotein B lipoproteins for subsequent uptake via the LDL receptor. In this study, we determined whether CETP can compensate for loss of adrenal SR-BI. Transgenic expression of human CETP (CETP Tg) in SR-BI knockout (KO) mice increased adrenal HDL-CE clearance from 33–58% of the control value. SR-BI KO/CETP Tg and SR-BI KO mice displayed adrenal hypertrophy due to equally high plasma adrenocorticotropic hormone levels. Adrenal cholesterol levels and plasma corticosterone levels were 38–52% decreased in SR-BI KO mice with and without CETP expression. SR-BI KO/CETP Tg mice also failed to increase their corticosterone level after lipopolysaccharide challenge, leading to an identical >4-fold increased tumor necrosis factor- response compared with controls. These data indicate that uptake of CE via other routes than SR-BI is not sufficient to generate the cholesterol pool needed for optimal adrenal steroidogenesis. In conclusion, we have shown that CETP-mediated transfer of HDL-CE is not able to reverse adrenal insufficiency in SR-BI knockout mice. Thus, SR-BI-mediated uptake of serum cholesterol is essential for optimal adrenal function.

Supplementary key words adrenals • cholesteryl ester transfer protein • high density lipoprotein • low density lipoprotein • cholesteryl ester • corticosterone • inflammation

Abbreviations: ACTH, adrenocorticotropic hormone; ApoB, apolipoprotein B; CEt, [³H]cholesteryl ether; CETP, cholesteryl ester transfer protein; Ct, threshold cycle number; HPRT, hypoxanthine guanine phosphoribosyl transferase; KO, knockout; SR-BI, scavenger receptor class B type I; TNF-a, tumor necrosis factor-; WT, wild-type

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