Bile acids inhibit glucocorticoid and mineralocorticoid metabolism. However bile acids may also influence hormone action by modulating steroidogenesis in the adrenal gland. In rodents adrenal cholesterol supply for steroidogenesis is derived from circulating HDL through the actions of scavenger receptor SR-B1. Since hepatic SR-B1 expression is known to be regulated by bile acids, we have investigated whether adrenal SR-B1 is similarly affected and, if so, whether adrenal lipid accumulation and key steroidogenic enzymes also change.
Male Wistar rats (n=8) were fed fat-free diet (Control) or fat-free diet supplemented with chenodeoxycholic acid (CDCA;1%w/w) for 4weeks achieving a 3-fold increase in plasma bile acids. Plasma corticosterone. aldosterone and renin were measured by RIA and ACTH by ELISA. Abundance of adrenal SR-B1, 11β-hydroxylase (Cyp11B1) and aldosterone synthase (Cyp11B2) mRNA were quantified by real-time PCR. Adrenals were stained for lipids and morphology using Oil Red O and H&E respectively. Data are treatment vs control; mean±S.E.M.;*=P<0.05.
SR-B1 mRNA abundance was elevated by 80%* following CDCA treatment. Adrenal gland mass was not affected but histological changes were observed principally within the cortex. Zona glomerulosa cells in glands from treated rats were more numerous but were generally smaller (0.18±0.007 vs 0.21±0.008 μm2*) and contained larger lipid droplets. These changes were accompanied by increased CYP11B2 expression (15.8±2.4×106 vs 8.2±1.5×106* Copies/μgRNA), higher circulating aldosterone (3501±218 vs 2206±137* pg/ml) levels and enhanced renin activity (24.14±3.93 vs 15.23±1.52* ng Ang I/ml/hr). Conversely CYP11B1 expression was decreased (8.1±1.6×106 vs 44.04±4.3×106× Copies/μgRNA) with reduced circulating corticosterone (52.6±7.4 vs 84.9±10.3* nM) and no change in ACTH (2.12±0.4 vs 1.40±0.6 pg/ml) or in the size of corticosterone-synthesizing zona fasciculata/reticularis cells.
Thus, elevated circulating bile acids, as occurs in jaundice or obesity can have a profound impact on the hypothalamic-pituitary-adrenal and renin-angiotensin-aldosterone axes. These effects are mediated in part by inhibitory effects on hepatic steroid metabolism but also by stimulatory effects on adrenal cholesterol supply for steroidogenesis via increased expression of adrenal SR-B1.
01 - 05 Apr 2006
European Society of Endocrinology