Human in vitro models of nonalcoholic fatty liver disease

Systems-oriented approaches involving integrated in vitro and in silico models are emerging as a basis for future risk assessment strategies to address the current challenge in chemical risk assessment of increased numbers of registered chemicals with no toxicological data. Liver toxicity poses a major concern in risk assessment as the liver is exposed to most xenobiotic compounds and their bioactive metabolites, making the liver susceptible to chemically induced liver diseases. Nonalcoholic fatty liver disease (NAFLD) is a rising global burden with an estimated prevalence of about 25% in the general population. Risk factors for NAFLD include metabolic disorders, genetics, drugs, and environmental exposures. To integrate in vitro data into computational models and use in vitro to in vivo extrapolation to systematically assess the risk of chemicals to induce NAFLD, sophisticated human cell models are needed. Reviewed here are characteristics and limitations of 2D and 3D monoculture and coculture human liver cell models, including microphysiological systems, in which NAFLD-relevant end points were addressed together with their results. The aim of this review is to inform selection of experimental test systems depending on the toxicological question to be addressed and to promote the further development of in vitro approaches that address existing technological gaps.