Molecular control of systemic bile acid homeostasis by the liver glucocorticoid receptor

Adam J. Rose, Mauricio Berriel Díaz, Anja Reimann, Johanna Klement, Tessa Walcher, Anja Krones-Herzig, Oliver Strobel, Jens Werner, Achim Peters, Anna Kleyman, Jan P. Tuckermann, Alexandros Vegiopoulos, Stephan Herzig

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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.

Original languageEnglish
Pages (from-to)123-130
Number of pages8
JournalCell Metabolism
Volume14
Issue number1
DOIs
Publication statusPublished - 6 Jul 2011
Externally publishedYes

Cite this

Rose, A. J., Díaz, M. B., Reimann, A., Klement, J., Walcher, T., Krones-Herzig, A., Strobel, O., Werner, J., Peters, A., Kleyman, A., Tuckermann, J. P., Vegiopoulos, A., & Herzig, S. (2011). Molecular control of systemic bile acid homeostasis by the liver glucocorticoid receptor. Cell Metabolism, 14(1), 123-130. https://doi.org/10.1016/j.cmet.2011.04.010