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Effect of bile duct ligation on bile acid composition in mouse serum and liver
Author(s) -
Zhang Youcai,
Hong JiYoung,
Rockwell Cheryl E.,
Copple Bryan L.,
Jaeschke Hartmut,
Klaassen Curtis D.
Publication year - 2012
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2011.02662.x
Subject(s) - cholestasis , taurocholic acid , liver injury , taurine , bile acid , ursodeoxycholic acid , medicine , bile duct , toxicity , cyp8b1 , biliary tract , endocrinology , chemistry , cholic acid , biochemistry , amino acid
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 ( BA s) in hepatocytes. Direct toxicity of BA s is currently the most accepted hypothesis for cholestatic liver injury. However, information on which bile acids are actually accumulating during cholestasis is limited. Aim 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 BA s. 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. BA s 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 BA s identified in serum and liver, only taurocholic acid ( TCA ), β‐muricholic acid (β MCA ) and Tβ MCA were substantially elevated representing >95% of these BA s over the entire time course. Although glycochenodeoxycholic acid and other conjugated BA s increased in BDL animals, the changes were several orders of magnitude lower compared with TCA , β MCA and Tβ MCA . A mixture of these BA s did not cause apoptosis or necrosis, but induced inflammatory gene expression in cultured murine hepatocytes. Conclusion The concentrations of cytotoxic BA s are insufficient to cause hepatocellular injury. In contrast, TCA , β MCA and Tβ MCA are able to induce pro‐inflammatory mediators in hepatocytes. Thus, BA s act as inflammagens and not as cytotoxic mediators after BDL in mice.