title: Prednisolone increases enterohepatic cycling of bile acids by induction of Asbt and promotes reverse cholesterol transport.
abstract: OBJECTIVE
  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 (12.5mg/kg/day) for 7days 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 enterohepatic 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.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands. Electronic address: c.out@umcg.nl.
authors.forename: Carolien
authors.initials: C
authors.lastname: Out
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands.
authors.forename: Arne
authors.initials: A
authors.lastname: Dikkers
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands.
authors.forename: Anke
authors.initials: A
authors.lastname: Laskewitz
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands.
authors.forename: Renze
authors.initials: R
authors.lastname: Boverhof
authors.affiliation: Department of Laboratory Medicine, Groningen, The Netherlands.
authors.forename: Claude
authors.initials: C
authors.lastname: van der Ley
authors.affiliation: Department of Laboratory Medicine, Groningen, The Netherlands.
authors.forename: Ido P
authors.initials: IP
authors.lastname: Kema
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: Wolters
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands.
authors.forename: Henkjan J
authors.initials: HJ
authors.lastname: Verkade
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands; Department of Laboratory Medicine, Groningen, The Netherlands.
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands.
authors.forename: Uwe J F
authors.initials: UJ
authors.lastname: Tietge
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatrics, Groningen, The Netherlands; Department of Laboratory Medicine, Groningen, The Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D004764:Enterohepatic Circulation; D006706:Homeostasis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D029363:Organic Anion Transporters, Sodium-Dependent / Q000096:biosynthesis*; D011239:Prednisolone / Q000494:pharmacology*; D027981:Symporters / Q000096:biosynthesis*
chemical_list: D001647:Bile Acids and Salts; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter; D002784:Cholesterol; D011239:Prednisolone
keywords: Apical sodium-dependent bile acid transporter (Asbt; Slc10a2); Atherosclerosis; Bile acids; Cardiovascular diseases; Choleresis; Cholestasis; Cholesterol; Farnesoid X receptor; Glucocorticoid receptor; Glucocorticoids; HDL; Prednisolone; Reverse cholesterol transport