title: Effect of bile duct ligation on bile acid composition in mouse serum and liver.
abstract: BACKGROUND
  Cholestatic liver diseases can be caused by genetic defects, drug toxicities, hepatobiliary malignancies or obstruction of the biliary tract. Cholestasis leads to accumulation of bile acids (BAs) in hepatocytes. Direct toxicity of BAs is currently the most accepted hypothesis for cholestatic liver injury. However, information on which bile acids are actually accumulating during cholestasis is limited.
  
  
  OBJECTIVE
  To assess the BA composition in liver and serum after bile duct ligation (BDL) in male C57Bl/6 mice between 6 h and 14 days and evaluate toxicity of the most abundant BAs.
  
  
  RESULTS
  Bile acid concentrations increased in liver (27-fold) and serum (1400-fold) within 6 h after surgery and remained elevated up to 14 days. BAs in livers of BDL mice became more hydrophilic than sham controls, mainly because of increased 6β-hydroxylation and taurine conjugation. Among the eight unconjugated and 16 conjugated BAs identified in serum and liver, only taurocholic acid (TCA), β-muricholic acid (βMCA) and TβMCA were substantially elevated representing >95% of these BAs over the entire time course. Although glycochenodeoxycholic acid and other conjugated BAs increased in BDL animals, the changes were several orders of magnitude lower compared with TCA, βMCA and TβMCA. A mixture of these BAs did not cause apoptosis or necrosis, but induced inflammatory gene expression in cultured murine hepatocytes.
  
  
  CONCLUSIONS
  The concentrations of cytotoxic BAs are insufficient to cause hepatocellular injury. In contrast, TCA, βMCA and TβMCA are able to induce pro-inflammatory mediators in hepatocytes. Thus, BAs act as inflammagens and not as cytotoxic mediators after BDL in mice.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Youcai
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Hong
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Rockwell
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Copple
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017734:Bile Ducts, Extrahepatic / Q000601:surgery; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D001651:Cholestasis, Extrahepatic / Q000097:blood* / Q000209:etiology / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D015815:Cell Adhesion Molecules; D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger
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