Endocrine Abstracts

Background and aims: Bile acids regulate cholesterol metabolism and the digestive system. They are conserved through enterohepatic circulation, a glucocorticoid-modulated process. We investigated whether the regeneration of active glucocorticoid by 11β-hydroxysteroid dehydrogenase type one (11β-HSD1) affects bile acid release and enterohepatic transport after re-feeding.

Methods: Bile acid turnover was assessed in global (Hsd11b11^−/−), liver-specific knockout (Hsd11b1^LKO/LKO) mice as well as mice with liver-specific over-expression of 11β-HSD1 (Hsd11b1^LOE/LOE), compared with their respective genetic controls (C57Bl/6 and ‘floxed’ Hsd11b1^F/F littermates). Adult (12 week) male, chow-fed mice (n=8/group), were either fasted for 4 h or fasted for 4 h then re-fed 4 h. Serum bile acids were measured spectrophotometrically and corticosterone by ELISA. Body and tissue weights, food and fluid intake were recorded.

Results: Serum bile acids remained high in re-fed Hsd11b1^−/− mice (fasted, 30+9 nM vs refed, 24+12 nM) in contrast to C57BL/6 mice (fasted, 3.8+1.3 nM vs refed, 62.5+7.6 nM, P<0.0001). Hsd11b1^LKO/LKO mice replicated all the effects seen in Hsd111b1^−/− mice whilst Hsd11b1^LOE/LOE was identical to C57BL/6. Hsd11b1^−/− mice failed to show the normal gall bladder weight change upon re-feeding compared to C57BL/6 (C57BL/6: fasted 100+6% vs re-fed, 49.6%+8, P<0.0001; Hsd11b1^−/−: fasted, 96+6.5% vs refed 92+7.8%). Hsd11b1^−/− mice showed reduced food and water intake following re-feeding (Food: C57BL/6 100+7%, vs Hsd11b1^−/− 72.3+14% P<0.05. Water: C57BL/6 100+15% vs Hsd11b1^−/− 63+4%, P<0.001). Basal, noon and evening corticosterone levels showed a normal circadian rhythm but did not differ between genotypes.

Conclusions: These data suggest that hepatic 11β-HSD1 deficiency reduces enterohepatic circulation of bile acids by preventing gall bladder emptying. Thus inhibition of hepatic11β-HSD1 may lead to cholestasis. Whether acute changes in food and water intake are directly caused by 11β-HSD1 activity or are secondary to changes in bile acid homeostasis is not clear.

Declaration of funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.