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Title: Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis

Accumulation of bile acids is a major mediator of cholestatic liver injury. Recent studies indicate bile acid composition between humans and rodents is dramatically different, as humans have a higher percent of glycine conjugated bile acids and increased chenodeoxycholate content, which increases the hydrophobicity index of bile acids. This increase may lead to direct toxicity that kills hepatocytes, and promotes inflammation. To address this issue, this study assessed how pathophysiological concentrations of bile acids measured in cholestatic patients affected primary human hepatocytes. Individual bile acid levels were determined in serum and bile by UPLC/QTOFMS in patients with extrahepatic cholestasis with, or without, concurrent increases in serum transaminases. Bile acid levels increased in serum of patients with liver injury, while biliary levels decreased, implicating infarction of the biliary tracts. To assess bile acid-induced toxicity in man, primary human hepatocytes were treated with relevant concentrations, derived from patient data, of the model bile acid glycochenodeoxycholic acid (GCDC). Treatment with GCDC resulted in necrosis with no increase in apoptotic parameters. This was recapitulated by treatment with biliary bile acid concentrations, but not serum concentrations. Marked elevations in serum full-length cytokeratin-18, high mobility group box 1 protein (HMGB1), and acetylated HMGB1 confirmed inflammatory necrosismore » in injured patients; only modest elevations in caspase-cleaved cytokeratin-18 were observed. These data suggest human hepatocytes are more resistant to human-relevant bile acids than rodent hepatocytes, and die through necrosis when exposed to bile acids. These mechanisms of cholestasis in humans are fundamentally different to mechanisms observed in rodent models. - Highlights: • Cholestatic liver injury is due to cytoplasmic bile acid accumulation in hepatocytes. • Primary human hepatocytes are resistant to BA-induced injury compared to rodents. • Primary human hepatocytes largely undergo necrosis in response to BA toxicity. • Cholestatic liver injury in vivo is predominantly necrotic with minor apoptosis. • Rodent models of bile acid toxicity may not recapitulate the injury in man.« less
Authors:
;  [1] ; ;  [2] ;  [3] ;  [1] ; ; ;  [4] ;  [5] ; ;  [2] ;  [1] ;  [3] ;  [1]
  1. Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)
  2. MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool (United Kingdom)
  3. Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States)
  4. Department of Surgery, University of Kansas Medical Center, Kansas City, KS (United States)
  5. Department of Pathology, University of Kansas Medical Center, Kansas City, KS (United States)
Publication Date:
OSTI Identifier:
22465712
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 283; Journal Issue: 3; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AMINOTRANSFERASES; APOPTOSIS; BILE; BILIARY TRACT; CHOLIC ACID; CONCENTRATION RATIO; GLYCINE; HUMAN POPULATIONS; INFLAMMATION; INJURIES; LEVELS; LIVER; LIVER CELLS; NECROSIS; PATIENTS; POLYPEPTIDES; RODENTS; TOXICITY