Nonalcoholic fatty liver disease (NAFLD), which is characterized by triglyceride deposition in hepatocytes resulting from imbalanced lipid homeostasis, is of increasing concern in Western countries, along with progression to nonalcoholic 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 M each) and/or with 10 ng/ml of the inflammatory mediator interleukin-6 (IL-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, and peroxisome proliferator-activated receptor (PPAR). 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. IL-6 exerted pronounced negative regulatory effects on basal as well as on PXR-, CAR-, and PPAR-, 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. The most striking effects of IL-6 and/or fatty acid treatment were observed in HepaRG cells after 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.

This article investigates the minimum level of religious observance expected of lay Christians by church authorities, and the degree to which legislation and procedures attempted to enforce these standards. 1 Once baptized, a person entered the community of the faithful; and the medieval church was as much accountable for the health and salvation of the ignorant, the ambivalent, the disobedient or distracted as they were of the devout. From the twelfth century, theologians, clerical authorities and the laity turned with concerted enthusiasm to the question of lay observance, advancing high ideals for lay commitment and expanding opportunities for lay participation. Yet while acting to elucidate and advance these qualities, the church was nevertheless mindful of the number of Christians who might fail to reach even basic standards. The resulting balance of the ideal and the possible, and the degree to which it reached and was enforced upon the less-enthusiastic laity is explored here through expectations for knowledge, observance of sacraments, and participation in regular duties such as church attendance, tithe-paying and fasting. The result was a complex ideal of lay observance that was balanced by a tolerance of laxity and even failure, and a system which increasingly exhorted specific expectations but was hesitant to define contumacy or disobedience in many but the most obdurate or scandalous cases.

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