Lithocholic acid feeding results in direct hepato-toxicity independent of neutrophil function in mice.

Abstract

Lithocholic acid (LCA) supplementation in the diet results in intrahepatic cholestasis and bile infarcts. Previously we showed that an innate immune response is critical for cholestatic liver injury in the bile duct ligated mice. Thus, the purpose of this study was to investigate the role of neutrophils in the mechanism of liver injury caused by feeding mice a diet containing LCA. C57BL/6 mice were given control or 1% LCA containing diet for 24-96 h and then examined for parameters of hepatotoxicity. Plasma ALT levels were significantly increased by 48 h after LCA feeding, which correlated with both neutrophil recruitment to the liver and upregulation of numerous pro-inflammatory genes. The injury was confirmed by histology. Deficiency in intercellular adhesion molecule-1 (ICAM-1) expression or inhibition of neutrophil function failed to protect against the injury. Bile acid levels were quantified in plasma and bile of LCA-fed mice after 48 and 96 h. Only the observed biliary levels of taurochenodeoxycholic acid and potentially tauro-LCA caused direct cytotoxicity in mouse hepatocytes. These data support the conclusion that neutrophil recruitment occurs after the onset of bile acid-induced necrosis in LCA-fed animals, and is not a primary mechanism of cell death when cholestasis occurs through accumulation of hydrophobic bile acids.

• Authors: Benjamin L Woolbright, Feng Li, Yuchao Xie, Anwar Farhood, Peter Fickert, Michael Trauner, Hartmut Jaeschke
• Journal: Toxicology letters (Toxicol Lett) Vol. 228 Issue 1 Pg. 56-66 (Jul 03 2014) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 24742700 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Bile Acids and Salts
• Membrane Glycoproteins
• Pirb protein, mouse
• Receptors, Immunologic
• Lithocholic Acid
• Cybb protein, mouse
• NADPH Oxidase 2
• NADPH Oxidases
• Caspases

Topics

• Animals
• Bile (metabolism)
• Bile Acids and Salts (metabolism)
• Blotting, Western
• Caspases (metabolism)
• Chemical and Drug Induced Liver Injury (metabolism, pathology)
• Cholestasis (chemically induced, pathology)
• Diet
• Hepatocytes (drug effects, metabolism)
• Immunohistochemistry
• Inflammation (genetics)
• Lithocholic Acid (metabolism, toxicity)
• Membrane Glycoproteins (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NADPH Oxidase 2
• NADPH Oxidases (genetics)
• Necrosis
• Neutrophils (drug effects)
• Real-Time Polymerase Chain Reaction
• Receptors, Immunologic (genetics)
• Up-Regulation (drug effects)