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Title: A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen

Abstract

Obesity and nonalcoholic fatty liver disease (NAFLD) can increase susceptibility to hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are poorly understood. For acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during NAFLD. The first aim of our study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, human HepaRG cells were incubated for one week with stearic acid or oleic acid, in the presence of different concentrations of insulin. Although cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids, CYP2E1 activity was significantly increased only by stearic acid. CYP2E1 activity was reduced by insulin and this effect was reproduced in cultured primary human hepatocytes. Next, APAP cytotoxicity was assessed in HepaRG cells with or without lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations showed that the loss of ATP and glutathione was almost always greater in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole, recovery of ATP was significantly higher in the presencemore » of stearate with low (2.5 mM) or high (20 mM) concentrations of APAP. Levels of APAP-glucuronide were significantly enhanced by insulin. Hence, HepaRG cells can be used as a valuable model of NAFLD to unveil important metabolic and hormonal factors which can increase susceptibility to drug-induced hepatotoxicity. - Highlights: • Nonalcoholic fatty liver disease (NAFLD) is frequent in obese individuals. • NAFLD can favor hepatotoxicity induced by some drugs including acetaminophen (APAP). • A model of NAFLD was set up by using HepaRG cells incubated with stearate or oleate. • Stearate-loaded HepaRG cells presented higher cytochrome P450 2E1 (CYP2E1) activity. • APAP cytotoxicity was stronger in steatotic HepaRG cells with higher CYP2E1 activity.« less

Authors:
;  [1];  [1];  [2];  [1];  [3];  [1]; ;  [1];  [2];  [1];  [3];  [1]
  1. INSERM, U991, Université de Rennes 1, Rennes (France)
  2. (France)
  3. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)
Publication Date:
OSTI Identifier:
22687888
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 292; 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; ATP; CONCENTRATION RATIO; CYTOCHROMES; ENZYMES; GLUTATHIONE; INJURIES; INSULIN; LIVER; LIVER CELLS; METABOLIC DISEASES; OCTADECANOIC ACID; OLEIC ACID; STEARATES; TRIGLYCERIDES

Citation Formats

Michaut, Anaïs, Le Guillou, Dounia, Moreau, Caroline, Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes, Bucher, Simon, McGill, Mitchell R., Martinais, Sophie, Gicquel, Thomas, Morel, Isabelle, Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes, Robin, Marie-Anne, Jaeschke, Hartmut, and Fromenty, Bernard, E-mail: bernard.fromenty@inserm.fr. A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen. United States: N. p., 2016. Web. doi:10.1016/J.TAAP.2015.12.020.
Michaut, Anaïs, Le Guillou, Dounia, Moreau, Caroline, Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes, Bucher, Simon, McGill, Mitchell R., Martinais, Sophie, Gicquel, Thomas, Morel, Isabelle, Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes, Robin, Marie-Anne, Jaeschke, Hartmut, & Fromenty, Bernard, E-mail: bernard.fromenty@inserm.fr. A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen. United States. doi:10.1016/J.TAAP.2015.12.020.
Michaut, Anaïs, Le Guillou, Dounia, Moreau, Caroline, Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes, Bucher, Simon, McGill, Mitchell R., Martinais, Sophie, Gicquel, Thomas, Morel, Isabelle, Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes, Robin, Marie-Anne, Jaeschke, Hartmut, and Fromenty, Bernard, E-mail: bernard.fromenty@inserm.fr. Mon . "A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen". United States. doi:10.1016/J.TAAP.2015.12.020.
@article{osti_22687888,
title = {A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen},
author = {Michaut, Anaïs and Le Guillou, Dounia and Moreau, Caroline and Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes and Bucher, Simon and McGill, Mitchell R. and Martinais, Sophie and Gicquel, Thomas and Morel, Isabelle and Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes and Robin, Marie-Anne and Jaeschke, Hartmut and Fromenty, Bernard, E-mail: bernard.fromenty@inserm.fr},
abstractNote = {Obesity and nonalcoholic fatty liver disease (NAFLD) can increase susceptibility to hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are poorly understood. For acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during NAFLD. The first aim of our study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, human HepaRG cells were incubated for one week with stearic acid or oleic acid, in the presence of different concentrations of insulin. Although cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids, CYP2E1 activity was significantly increased only by stearic acid. CYP2E1 activity was reduced by insulin and this effect was reproduced in cultured primary human hepatocytes. Next, APAP cytotoxicity was assessed in HepaRG cells with or without lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations showed that the loss of ATP and glutathione was almost always greater in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole, recovery of ATP was significantly higher in the presence of stearate with low (2.5 mM) or high (20 mM) concentrations of APAP. Levels of APAP-glucuronide were significantly enhanced by insulin. Hence, HepaRG cells can be used as a valuable model of NAFLD to unveil important metabolic and hormonal factors which can increase susceptibility to drug-induced hepatotoxicity. - Highlights: • Nonalcoholic fatty liver disease (NAFLD) is frequent in obese individuals. • NAFLD can favor hepatotoxicity induced by some drugs including acetaminophen (APAP). • A model of NAFLD was set up by using HepaRG cells incubated with stearate or oleate. • Stearate-loaded HepaRG cells presented higher cytochrome P450 2E1 (CYP2E1) activity. • APAP cytotoxicity was stronger in steatotic HepaRG cells with higher CYP2E1 activity.},
doi = {10.1016/J.TAAP.2015.12.020},
journal = {Toxicology and Applied Pharmacology},
number = ,
volume = 292,
place = {United States},
year = {Mon Feb 01 00:00:00 EST 2016},
month = {Mon Feb 01 00:00:00 EST 2016}
}