Feedback Inhibition of Human Scavenger Receptor Class B Type I Gene Expression by Glucocorticoid in Adrenal and Ovarian Cells

Abstract

Scavenger receptor class B type I (SR-BI) facilitates the reverse transport of excess cholesterol from peripheral tissues to the liver via high-density lipoproteins. In steroidogenic tissues, SR-BI supplies cholesterol for steroid hormone production. We show here that the transcription of the human SR-BI gene is subject to feedback inhibition by glucocorticoid in adrenal and ovarian cells. SR-BI mRNA levels were increased in adrenals from corticosterone-insufficient Crh(-/-) mice, whereas corticosterone replacement by oral administration inhibited SR-BI gene expression in these mice. SR-BI mRNA levels were increased in adrenals from wild-type mice treated with metyrapone, a drug that blocks corticosterone synthesis. Experiments in adrenocortical H295R and ovarian SKOV-3 cells using cycloheximide and siRNA-mediated gene silencing revealed that glucocorticoid-mediated inhibition of SR-BI gene transcription requires de novo protein synthesis and the glucocorticoid receptor (GR). No direct binding of GR to the SR-BI promoter could be demonstrated in vitro and in vivo, suggesting an indirect mechanism of repression of SR-BI gene transcription by GR in adrenal cells. Deletion analysis established that the region of the human SR-BI promoter between nucleotides -201 and -62 is sufficient to mediate repression by glucocorticoid. This region contains putative binding sites for transcriptional repressors that could play a role in SR-BI gene regulation in response to glucocorticoid. In summary, this is the first report showing that glucocorticoid suppress SR-BI expression suggesting that steroidogenic tissues maintain steroid hormone homeostasis by prohibiting SR-BI-mediated high-density lipoprotein cholesterol uptake when the endogenous levels of glucocorticoid are elevated.

Genetic studies in mice and humans reveal new physiological roles for the high-density lipoprotein receptor scavenger receptor class B type I

“…In further support of the notion that cholesterol delivered via scavenger receptor BI to the adrenals is a rate-limiting factor in adrenocortical glucocorticoid production, Mavridou et al [14] have now also shown that the expression of scavenger receptor BI in adrenocortical cells is subject to negative feedback control by glucocorticoids. They identified a glucocorticoid-responsive element in the proximal promoter of human scavenger receptor BI that confers repression of transcription upon treatment with the synthetic steroid dexamethasone.…”

“…by Mavridou et al [14], thus, suggest the involvement of the nuclear glucocorticoid receptor in the repression of scavenger receptor BI transcription. The exact mechanism behind the glucocorticoid-mediated negative feedback on scavenger receptor BI expression, however, remains to be established, as Sporstøl et al [15] have previously shown repression of scavenger receptor BI expression by dexamethasone in human HepG2 cells that exhibit very low glucocorticoid receptor expression levels.…”

Differential action of glucocorticoids on apolipoprotein E gene expression in macrophages and hepatocytes

“…Interestingly, apoAI and apoAII, two major protein constituents of HDL, are differentially regulated by dexamethasone, with the first having its hepatic expression elevated and the latter decreased [38]. Scavenger receptor class B type I was found to be down-regulated by glucocorticoids in adrenal and ovarian cells [39]. …”

The central CLOCK system and the stress axis in health and disease

“…199 Glucocorticoids suppress SR-BI expression, thus exerting another negative feedback action by reducing the adrenal gland synthesis of glucocorticoids. 200,201 As a consequence of these actions of glucocorticoids, plasma ACTH concentrations are high in patients with Addison's disease and are low in patients with Cushing's syndrome caused by a cortisol-secreting adrenal tumor or exogenous glucocorticoid administration.…”