title: 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.affiliation: Department of Pharmacology, Toxicology & Therapeutics, Kansas University Medical Center, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Woolbright
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, Kansas University Medical Center, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, Kansas University Medical Center, USA.
authors.forename: Yuchao
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Pathology, St. David's North Austin Medical Center, Austin, TX 78756, USA.
authors.forename: Anwar
authors.initials: A
authors.lastname: Farhood
authors.affiliation: Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine, Graz, Austria; Department of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Fickert
authors.affiliation: Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, Kansas University Medical Center, USA. Electronic address: hjaeschke@kumc.edu.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology*; D002779:Cholestasis / Q000139:chemically induced / Q000473:pathology; D004032:Diet; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics; D008095:Lithocholic Acid / Q000378:metabolism / Q000633:toxicity*; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics; D009336:Necrosis; D009504:Neutrophils / Q000187:drug effects*; D060888:Real-Time Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001647:Bile Acids and Salts; D008562:Membrane Glycoproteins; C105949:Pirb protein, mouse; D011971:Receptors, Immunologic; D008095:Lithocholic Acid; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D020169:Caspases
keywords: Bile acid hepatotoxicity; Cholestasis; Innate immunity; Lithocholic acid; Neutrophils
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