RT Journal Article
SR Electronic
T1 Regulation of drug metabolism by the interplay of inflammatory signaling, steatosis, and xeno-sensing receptors in HepaRG cells
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.117.078675
DO 10.1124/dmd.117.078675
A1 Norman Tanner
A1 Lisa Kubik
A1 Claudia Luckert
A1 Maria Thomas
A1 Ute Hofmann
A1 Ulrich M. Zanger
A1 Linda Bohmert
A1 Alfonso Lampen
A1 Albert Braeuning
YR 2018
UL http://dmd.aspetjournals.org/content/early/2018/01/12/dmd.117.078675.abstract
AB Non-alcoholic fatty liver disease (NAFLD), characterized by triglyceride deposition in hepatocytes due to imbalanced lipid homeostasis, is of increasing concern in Western countries, with progression to non-alcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. Previous studies suggest a complex, mutual influence of hepatic fat accumulation, NASH-related inflammatory mediators, and drug-sensing receptors regulating xenobiotic metabolism. Here, we investigated the suitability of human HepaRG hepatocarcinoma cells as a model for NAFLD and NASH. Cells were incubated for up to 14 days with an oleate/palmitate mixture (125 μM each), and/or with 10 ng/mL of the inflammatory mediator interleukin-6. Effects of these conditions on the regulation of drug metabolism were studied using xenobiotic agonists of the aryl hydrocarbon receptor (AHR), pregnane-X-receptor (PXR), constitutive androstane receptor (CAR), nuclear factor (erythroid-derived 2)-like 2 (NRF2), and peroxisome proliferator-activated receptor α (PPARα). Results underpin the suitability of HepaRG cells for NAFLD- and NASH-related research and constitute a broad-based analysis of the impact of hepatic fatty acid accumulation and inflammation on drug metabolism and its inducibility by xenobiotics. Interleukin-6 exerted pronounced negative regulatory effects on basal as well as on PXR-, CAR-, PPARα-, but not AHR-dependent induction of drug-metabolizing enzymes. This inhibition was related to diminished transactivation potential of the respective receptors, rather than to reduced transcription of nuclear receptor-encoding mRNAs. Most striking effects of interleukin-6 and/or fatty acid treatment were observed in HepaRG cells following 14 days of treatment, making these cultures appear a suitable model for studying the relationship of fatty acid accumulation, inflammation and xenobiotic-induced drug metabolism.