Impact of dietary chenodeoxycholic acid on the hypothalamic-pituitary-adrenal axis in rats
AD McNeilly, BR Walker & R Andrew
Alterations in the rate of glucocorticoid(GC) metabolism induce compensatory changes in GC secretion under the control of the hypothalamic-pituitary-adrenal (HPA) axis. The principal routes of metabolic clearance of GCs are by hepatic A-ring reduction however the regulation of these enzymes is poorly understood. Recently we and others have demonstrated that bile acids act as potent inhibitors of GC metabolism by 5beta-reductase and 11beta-hydroxysteroid dehydrogenases in vitro. The aim of this study was to determine the effects of dietary bile acids on GC metabolism and activation of the HPA axis in vivo.
Male Wistar rats (4-6 weeks, n=8/group) were fed chenodeoxycholic acid (CDCA, 1% w/w chow) or control diet for 4 weeks. The HPA axis was assessed by acute restraint stress (20mins). Plasma corticosterone and ACTH were measured by radioimmunoassay. mRNA for cholesterol 7alpha-hydroxylase (Cyp7A1) was quantified by Northern blot, corrected for U1. Data are mean plus/minus SEM, *=p<0.05; ns=not significant.
CDCA reduced Cyp7A1 mRNA levels (1.35 plus/minus 0.17 vs 0.70 plus/minus 0.09*AU) and increased HDL cholesterol concentrations (1.33 plus/minus 0.08 vs 1.59 plus/minus 0.09*mM). In addition CDCA significantly reduced adrenal weight (0.082 plus/minus 0.006 vs 0.066 plus/minus 0.005*mg/g body weight) but not thymus weight (0.73 plus/minus 0.04 vs 0.69 plus/minus 0.03g; ns). Corticosterone (78 plus/minus 19 vs 82 plus/minus 26nM; ns) and ACTH concentrations (27 plus/minus 6 vs 24 plus/minus 5pg/ml; ns) were not different at baseline. However following acute restraint stress, the area under the curve of Corticosterone concentrations was increased and the return to basal levels attenuated following CDCA (AUC 40-120 mins: 24203 plus/minus 4350 vs 41161 plus/minus 5540*nM/min).
In summary, dietary administration of CDCA influences HPA axis performance, probably by impairing metabolic clearance of GCs. The elevated levels of bile acids which occur post-prandially or in pathological conditions may therefore influence circulating and intra-hepatic GC levels.