title: Molecular control of systemic bile acid homeostasis by the liver glucocorticoid receptor.
abstract: Systemic bile acid (BA) homeostasis is a critical determinant of dietary fat digestion, enterohepatic function, and postprandial thermogenesis. However, major checkpoints for the dynamics and the molecular regulation of BA homeostasis remain unknown. Here we show that hypothalamic-pituitary-adrenal (HPA) axis impairment in humans and liver-specific deficiency of the glucocorticoid receptor (GR) in mice disrupts the normal changes in systemic BA distribution during the fasted-to-fed transition. Fasted mice with hepatocyte-specific GR knockdown had smaller gallbladder BA content and were more susceptible to developing cholesterol gallstones when fed a cholesterol-rich diet. Hepatic GR deficiency impaired liver BA uptake/transport via lower expression of the major hepatocyte basolateral BA transporter, Na(+)-taurocholate transport protein (Ntcp/Slc10a1), which affected dietary fat absorption and brown adipose tissue activation. Our results demonstrate a role of the HPA axis in the endocrine regulation of BA homeostasis through the liver GR control of enterohepatic BA recycling.
authors: Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ) Heidelberg, Germany. a.rose@dkfz.de
authors: Adam J
authors: AJ
authors: Rose
authors: Mauricio
authors: M
authors: Berriel Díaz
authors: Anja
authors: A
authors: Reimann
authors: Johanna
authors: J
authors: Klement
authors: Tessa
authors: T
authors: Walcher
authors: Anja
authors: A
authors: Krones-Herzig
authors: Oliver
authors: O
authors: Strobel
authors: Jens
authors: J
authors: Werner
authors: Achim
authors: A
authors: Peters
authors: Anna
authors: A
authors: Kleyman
authors: Jan P
authors: JP
authors: Tuckermann
authors: Alexandros
authors: A
authors: Vegiopoulos
authors: Stephan
authors: S
authors: Herzig
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism* / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D029363:Organic Anion Transporters, Sodium-Dependent; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D027981:Symporters; C071908:sodium-bile acid cotransporter