title: Glucocorticoid treatment alters systemic bile acid homeostasis by regulating the biosynthesis and transport of bile salts.
abstract: BACKGROUND
  Dysregulation of systemic bile acid homeostasis can lead to cholestatic liver diseases and metabolic syndromes. As important anti-inflammatory and immunosuppressive drugs, synthetic glucocorticoids (GCs) are used to treat several cholestatic disorders, including biliary atresia (BA), because of their effects on the regulation of bile acid metabolism. However, the molecular mechanisms that underlie GCs regulation of bile acid homeostasis remain unclear.
  
  
  OBJECTIVE
  To provide a mechanistic basis for the effects of GCs on bile acid homeostasis.
  
  
  METHODS
  Male rats were treated with methylprednisolone for 7 days with slow-release osmotic pumps under physiological and cholestatic status that was induced by bile duct ligation (BDL). Expression of glucocorticoid receptor (GR) and genes related to bile acid metabolism was investigated using western blotting, qRT-PCR and immunohistochemistry.
  
  
  RESULTS
  We show here that sustained treatment with GCs in rats disrupts the normal changes in systemic bile acid distribution by elevating plasma bile acid levels and reducing faecal bile acid loss. Treatment with GCs stimulated bile acid absorption in the ileum by increasing expression of the apical sodium-dependent bile acid transporter (Asbt). Concomitantly, administration of GCs enhanced liver bile acid uptake by increasing the expression of the major hepatocyte basolateral bile transporter (Ntcp). The reduced expression of a bile acid synthesis rate-controlling enzyme, Cyp7a1, suggests that treatment with GCs suppressed hepatic bile acid synthesis.
  
  
  CONCLUSIONS
  Our study provides evidence that GCs can increase enterohepatic bile acid circulation through regulation of the biosynthesis and transport of bile salts, which suggests that plasma bile acid levels should be monitored during treatment with GCs in patients with BA.
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute for Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Weihui
authors.initials: W
authors.lastname: Yan
authors.affiliation: Shanghai Institute for Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
authors.forename: Kejun
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute for Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China. Electronic address: caiw1978@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Cai
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood*; D001652:Bile Ducts / Q000601:surgery; D001656:Biliary Atresia / Q000235:genetics*; D045744:Cell Line, Tumor; D002675:Child, Preschool; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007223:Infant; D008026:Ligation; D008099:Liver / Q000378:metabolism; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters / Q000235:genetics / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; C496502:FOXA2 protein, human; D005938:Glucocorticoids; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; D051542:Hepatocyte Nuclear Factor 3-beta; C071908:sodium-bile acid cotransporter; C553219:CYP7A1 protein, human; C532838:CYP7A1 protein, rat; D002790:Cholesterol 7-alpha-Hydroxylase; D008775:Methylprednisolone
keywords: Bile acid; Biliary atresia; Glucocorticoid receptor; Glucocorticoids; Homeostasis