title: 11β-Hydroxysteroid dehydrogenase-1 is involved in bile acid homeostasis by modulating fatty acid transport protein-5 in the liver of mice.
abstract: 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.
authors: Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors: Carlos A
authors: CA
authors: Penno
authors: Centre for Endocrinology Diabetes and Metabolism (CEDAM), Institute of Biomedical Research, Medical School Building, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors: Stuart A
authors: SA
authors: Morgan
authors: Joint Research Division, Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH), Heidelberg University, Network Aging Research, University Hospital Heidelberg, Germany.
authors: Adam J
authors: AJ
authors: Rose
authors: Joint Research Division, Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg, Center for Molecular Biology (ZMBH), Heidelberg University, Network Aging Research, University Hospital Heidelberg, Germany.
authors: Stephan
authors: S
authors: Herzig
authors: Centre for Endocrinology Diabetes and Metabolism (CEDAM), Institute of Biomedical Research, Medical School Building, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors: Gareth G
authors: GG
authors: Lavery
authors: Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
authors: Alex
authors: A
authors: Odermatt
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