Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 283, Issue 3, Pages 168-177Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2015.01.015
Keywords
Bile acids; Obstructive cholestasis; Primary human hepatocytes; Biomarkers; Inflammation; HMGB1
Categories
Funding
- CTSA grant from NCATS
- Heartland Institute for Clinical and Translational Research [UUTR000001, UL1RR033179]
- National Institutes of Health [R01 DK070195, R01 AA12916, R01 GM077336]
- National Center for Research Resources [5P20RR021940-07]
- National Institute of General Medical Sciences of the National Institutes of Health [8 P20 GM103549-07]
- Training Program in Environmental Toxicology from the National Institute of Environmental Health Sciences [T32 ES007079-26A2]
- UK Medical Research Council [G0700654]
- MRC Integrative Toxicology Training Program
- Wellcome Trust
- MRC [G0700654, MR/L006758/1] Funding Source: UKRI
- Medical Research Council [MR/L006758/1, G0700654, 1610940] Funding Source: researchfish
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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 biliaty bile acid concentrations, but not serum concentrations. Marked elevations in serum full-length cytokeratin-18, high mobility group box! protein (HMGB1), and acetylated HMGB1 confirmed inflammatory necrosis 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. (C) 2015 Elsevier Inc. All rights reserved.
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