TY - JOUR
T1 - Prednisolone increases enterohepatic cycling of bile acids by induction of Asbt and promotes reverse cholesterol transport
AU - Out, Carolien
AU - Dikkers, Arne
AU - Laskewitz, Anke
AU - Boverhof, Renze
AU - van der Ley, Claude
AU - Kema, Ido P.
AU - Wolters, Henk
AU - Havinga, Rick
AU - Verkade, Henkjan J.
AU - Kuipers, Folkert
AU - Tietge, Uwe J. F.
AU - Groen, Albert K.
PY - 2014
Y1 - 2014
N2 - Background & Aims: Glucocorticoids, produced by the adrenal gland under control of the hypothalamic-pituitary-adrenal axis, exert their metabolic actions largely via activation of the glucocorticoid receptor (GR). Synthetic glucocorticoids are widely used as anti-inflammatory and immunosuppressive drugs but their application is hampered by adverse metabolic effects. Recently, it has been shown that GR may regulate several genes involved in murine bile acid (BA) and cholesterol metabolism, yet the physiological relevance hereof is controversial. The aim of this study is to provide a mechanistic basis for effects of prednisolone on BA and cholesterol homeostasis in mice. Methods: Male BALB/c mice were treated with prednisolone (12.5 mg/kg/day) for 7 days by subcutaneous implantation of slow-release pellets, followed by extensive metabolic profiling. Results: Sustained prednisolone treatment induced the expression of the apical sodium-dependent bile acid transporter (Asbt) in the ileum, which stimulated BA absorption. This resulted in elevated plasma BA levels and enhanced biliary BA secretion. Concomitantly, both biliary cholesterol and phospholipid secretion rates were increased. Enhanced BA reabsorption suppressed hepatic BA synthesis, as evident from hepatic gene expression, reduced plasma C4 levels and reduced fecal BA loss. Plasma HDL cholesterol levels were elevated in prednisolone-treated mice, which likely contributed to the stimulated flux of cholesterol from intraperitoneally injected macrophage foam cells into feces. Conclusions: Sustained prednisolone treatment increases entero-hepatic recycling of BA, leading to elevated plasma levels and reduced synthesis in the absence of cholestasis. Under these conditions, prednisolone promotes macrophage-derived reverse cholesterol transport. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved
AB - Background & Aims: Glucocorticoids, produced by the adrenal gland under control of the hypothalamic-pituitary-adrenal axis, exert their metabolic actions largely via activation of the glucocorticoid receptor (GR). Synthetic glucocorticoids are widely used as anti-inflammatory and immunosuppressive drugs but their application is hampered by adverse metabolic effects. Recently, it has been shown that GR may regulate several genes involved in murine bile acid (BA) and cholesterol metabolism, yet the physiological relevance hereof is controversial. The aim of this study is to provide a mechanistic basis for effects of prednisolone on BA and cholesterol homeostasis in mice. Methods: Male BALB/c mice were treated with prednisolone (12.5 mg/kg/day) for 7 days by subcutaneous implantation of slow-release pellets, followed by extensive metabolic profiling. Results: Sustained prednisolone treatment induced the expression of the apical sodium-dependent bile acid transporter (Asbt) in the ileum, which stimulated BA absorption. This resulted in elevated plasma BA levels and enhanced biliary BA secretion. Concomitantly, both biliary cholesterol and phospholipid secretion rates were increased. Enhanced BA reabsorption suppressed hepatic BA synthesis, as evident from hepatic gene expression, reduced plasma C4 levels and reduced fecal BA loss. Plasma HDL cholesterol levels were elevated in prednisolone-treated mice, which likely contributed to the stimulated flux of cholesterol from intraperitoneally injected macrophage foam cells into feces. Conclusions: Sustained prednisolone treatment increases entero-hepatic recycling of BA, leading to elevated plasma levels and reduced synthesis in the absence of cholestasis. Under these conditions, prednisolone promotes macrophage-derived reverse cholesterol transport. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved
U2 - https://doi.org/10.1016/j.jhep.2014.03.025
DO - https://doi.org/10.1016/j.jhep.2014.03.025
M3 - Article
C2 - 24681341
SN - 0168-8278
VL - 61
SP - 351
EP - 357
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 2
ER -