Endocrine Abstracts (2011) 26 OC5.1

HDL receptor SR-BI dysfunction is associated with a diminished adrenal glucocorticoid output in mice and man

M Hoekstra1, M Vergeer2, R B Hildebrand1, R J van der Sluis1, J J Kastelein2, M Van Eck1, J A Kuivenhoven2 & T J C Van Berkel1

1Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands; 2Department of Vascular Biology, Amsterdam Medical Center, Amsterdam, The Netherlands.

Adrenal-derived glucocorticoids originate from their precursor cholesterol. Scavenger receptor BI (SR-BI) is a major high-density lipoprotein (HDL) receptor that mediates the selective uptake of cholesteryl esters (CE) from this lipoprotein in the circulation. In our present studies in SR-BI knockout (KO) mice and human carriers of a functional mutation in the extracellular domain of SR-BI (P297S), we determined whether SR-BI-mediated uptake of HDL-CE is required for adrenal glucocorticoid production.

Impaired uptake of HDL-CE in SR-BI knockout mice induced depletion of adrenal lipid stores and adrenal hypertrophy. Basal steroidogenesis was, however, not affected by murine SR-BI deficiency. In contrast, fasting- and lipopolysaccharide (LPS)-induced plasma corticosterone levels were markedly lower in SR-BI KO mice compared to controls, which coincided with fasting hypoglycemia and an increased susceptibility to inflammation. A compensatory 2-fold increase in hepatic and plasma corticosteroid-binding globulin (CBG) and >2-fold higher ACTH levels were detected. ‘Humanizing’ SR-BI KO mice through transgenic expression of human cholesteryl ester transfer protein (CETP; mice are naturally CETP deficient) partially restored CE delivery to the adrenals due to transfer of CE from HDL to apoB-containing lipoproteins for uptake via the adrenal LDL receptor. However, CETP was unable to rescue the glucocorticoid insufficiency phenotype in SR-BI KO mice. In parallel, human heterozygotes for the SR-BI P297S mutation exhibited a diminished urinary excretion of most steroids in the context of higher plasma HDL-cholesterol and CBG levels. ACTH (tetracosactin) stimulation tests revealed unchanged baseline plasma levels of free cortisol, while the percentage increase in free cortisol levels following tetracosactin stimulation was significantly lower in carriers (127 vs 223% in controls).

In conclusion, our studies show that disruption of SR-BI function is associated with a diminished adrenal glucocorticoid output in mice and man and suggest that HDL fulfils a thus far unanticipated role in human adrenal steroid synthesis.

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