11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) plays a key role in glucocorticoid receptor (GR) activation. Besides, it metabolizes some oxysterols and bile acids (BAs). The GR regulates BA homeostasis; however, the impact of impaired 11β-HSD1 activity remained unknown. We profiled plasma and liver BAs in liver-specific and global 11β-HSD1-deficient mice. 11β-HSD1-deficiency resulted in elevated circulating unconjugated BAs, an effect more pronounced in global than liver-specific knockout mice. Gene expression analyses revealed decreased expression of the BA-CoA ligase Fatp5, suggesting impaired BA amidation. Reduced organic anion-transporting polypeptide-1A1 (Oatp1a1) and enhanced organic solute-transporter-β (Ostb) mRNA expression were observed in livers from global 11β-HSD1-deficient mice. The impact of 11β-HSD1-deficiency on BA homeostasis seems to be GR-independent because intrahepatic corticosterone and GR target gene expression were not substantially decreased in livers from global knockout mice. Moreover, Fatp5 expression in livers from hepatocyte-specific GR knockout mice was unchanged. The results revealed a role for 11β-HSD1 in BA homeostasis.
Keywords: 11β-Hydroxysteroid dehydrogenase; 11β-hydroxysteroid dehydrogenase 1, 11β-HSD1; BA coenzyme A: amino acid N-acyltransferase, Baat; Bile acid conjugation; Bile acid transport; Bile acids; Glucocorticoids; Na+-taurocholate cotransporting polypeptide, Ntcp; Organic anion-transporting polypeptide, Oatp; Organic solute transporter, Ost; bile acids, BAs; cholesterol 7α-hydroxylase, Cyp7a1; farnesoid X receptor, Fxr; fatty acid transport protein, Fatp; glucocorticoid receptor, GR; short heterodimer partner, Shp; sterol-regulatory element-binding protein 1C, Srebp1c.