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

Abstract

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-a 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.-Hoekstra, M., D. Ye, R. B. Hildebrand, Y. Zhao, B. Lammers, M. Stitzinger, J. Kuiper, T. J. C. Van Berkel, and M. Van Eck. Scavenger receptor class B type I-mediated uptake of serum cholesterol is essential for optimal adrenal glucocor ticoid production.

LCAT deficiency in mice is associated with a diminished adrenal glucocorticoid function

“…However, the difference in leukocyte glucocorticoid insuffi ciency and endotoxemia susceptibility between the LCAT and SR-BI knockout mice seems to rely on a HDL-cholesteryl ester-independent corticosterone response. SR-BI knockout mice fail to increase their plasma corticosterone levels in response to LPS exposure ( 9,28 ), whereas the present study shows that LCAT KO mice are able to increase, albeit to a lower extent, their plasma glucocorticoid levels in response to endotoxemia. Both our LCAT KO mice and SR-BI KO mice ( 9 ) display an increase in the adrenal relative expression level of the LDL receptor, the primary protein involved in the clearance of apoB-containing lipoproteins such as VLDL and LDL.…”

“…Our previous data from SR-BI KO mice that lack a functional HDL receptor indicated that disrupted adrenal uptake of cholesteryl esters from HDL is associated with glucocorticoid insuffi ciency because these mice display ( 1 ) a lowered hepatic glucocorticoid signaling and ( 2 ) an enhanced susceptibility to endotoxemia ( 9,10,28 ). In the current study we observed that LCAT KO mice that completely lack HDL-cholesteryl esters also display diminished glucocorticoid signaling in hepatocytes because they exhibit a lowered hepatic APOA4 mRNA expression level and a compensatory up-regulation of liver corticosteroid binding globulin expression.…”

Adrenocortical LDL receptor function negatively influences glucocorticoid output

“…In accordance with a stress-induced stimulation of the steroidogenic machinery, expression of rate-limiting enzymes involved in the mobilization of cholesterol, such as SR-BI (Ct: 21.4G1.1) and STAR (Ct: 23.2G1.1), and subsequent conversion into corticosterone, i.e., CYP11A1 (Ct: 20.9G0.9), HSD3B2 (Ct: 26.3G0.9), CYP21A1 (Ct: 21.6G0.7), and CYP11B1 (Ct: 25.4G1.3), could be readily detected in LDLRK adrenal transplants under fasting conditions. Stimulation of the expression of the HDL receptor SR-BI is an obligatory event in the ACTH-mediated adrenal stress response to maintain functional adrenal cholesterol stores , Hoekstra et al 2008, 2009. Interestingly, as can be seen in Fig.…”

“…A genetic defect in proteins involved in the formation and cellular uptake of HDL-cholesteryl esters is associated with a diminished adrenal glucocorticoid output in experimental mouse models (Cai et al 2008, Hoekstra et al 2008, 2009) as well as in humans (Vergeer et al 2011, Bochem et al 2013. HDL-cholesterol thus appears to be of crucial importance for an optimal production of glucocorticoids by the adrenals in vivo.…”

“…Importantly, lowering LDLcholesterol levels in FH patients by lovastatin (mevinolin) treatment does not further affect the adrenal glucocorticoid function (Laue et al 1987). Furthermore, stimulation of the alternative LDL/LDLR route of cholesterol delivery to the adrenals by introducing human cholesteryl ester transfer protein in mice genetically lacking the HDL receptor SR-BI is also not able to reverse the associated glucocorticoid insufficiency (Hoekstra et al 2009). Based on these combined findings, it can be suggested that the LDL/LDLR route does not play a major role in the supply of the steroidogenic cholesterol substrate in vivo.…”