Scavenger receptor BI-mediated uptake of serum cholesterol is essential for optimal adrenal glucocorticoid production

Menno Hoekstra, 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, Leiden, Zuid-Holland 2300 RA

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

Impaired scavenger receptor BI (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 ApoB-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% to 58% of the control value. SR-BI KO/CETP Tg and SR-BI KO mice displayed adrenal hypertrophy due to equally high plasma ACTH 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 LPS challenge, leading to an identical >4-fold increased TNF-alpha response as compared to 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.

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