Endocrine Abstracts (2008) 15 P303

Mechanisms of altered glucocorticoid metabolism and adrenal insufficiency in cholestatic liver disease

AD McNeilly1, DEW Livingstone1, SM McKenzie2, E Davies2, O Skott3, H Thiesson3, CJ Kenyon1, BR Walker1 & R Andrew1

1University of Edinburgh, Edinburgh, UK; 2University of Glasgow, Glasgow, UK; 3University of Odense, Odense, Denmark.

Glucocorticoids mediate the stress response, regulated via the hypothalamic–pituitary–adrenal (HPA) axis. The HPA axis is down-regulated and its responsiveness to stress is impaired in cholestasis. The mechanisms are unknown, but may involve reduced glucocorticoid clearance. Hepatic 5beta-reductase is involved in glucocorticoid inactivation and bile acid biosynthesis. We showed previously that bile acids are potent competitive inhibitors and transcriptional regulators of 5beta-reduction of glucocorticoids, and that dietary administration of bile acids to rats reduces urinary excretion of 5beta-reduced metabolites of corticosterone and alters responses of the HPA axis to stress. Here, we studied the effects of pathological accumulation of bile acids upon glucocorticoid metabolism and the HPA axis.

Male Wistar rats (150–200 g; n=8/group) were studied 5 weeks after bile duct ligation (BDL) or sham surgery. Enzyme activities and transcript abundances were quantified using radio-HPLC and real-time qPCR, respectively. Corticosterone concentrations were measured by RIA. Data are mean±S.E.M., BDL versus sham; *P<0.05; **P<0.01.

Hepatic 5beta-reductase activity was reduced following BDL (3.3±0.3* vs 18±1.8 pmol/mg per hour respectively). Transcript abundances of hepatic 5beta-reductase, 5alpha-reductase 1 and 3alpha-hydroxysteroid dehydrogenase were also reduced (10.6*, 5.9**, 12.9**-fold respectively). Although basal plasma corticosterone concentrations (144±39.6 vs 112±18.5 nM) and adrenal gland size (16.6±0.8 vs 20.7±2.5 mg/100 g) were unaltered by BDL, adrenal transcript abundance of Scavenger receptor B1 (0.7±0.14* vs 1.2±0.13 vs beta-actin) and CYP11B1 (57.4±0.76* vs 82.5±0.74 mRNA copy number×106), responsible for HDL cholesterol uptake and corticosterone synthesis respectively, were significantly down-regulated in BDL animals. However a compensatory increase in adrenal HMG-CoA reductase mRNAs, driving cholesterol synthesis, was also observed (3-fold**).

In summary, BDL suppressed hepatic glucocorticoid metabolism and reduced HDL cholesterol uptake and glucocorticoid synthesise in the adrenal gland. These mechanisms may contribute to the impaired responsiveness of the HPA axis to stress in cholestasis.

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