Chip model for research of non-alcoholic fatty liver disease
2021
University of Central Florida, Orlando, USA
The development of non-alcoholic fatty liver disease (NAFDL) is associated with a manifestation of metabolic syndrome and is therefore associated with various metabolic disorders and concomitant diseases (type 2 diabetes, obesity, lipid metabolism disorder, arterial hypertension), which complicate the investigation of causes and effective drug therapy. In 1 in 5 people, relatively harmless fatty liver disease (NAFL) can develop into pathological steatohepatitis (NASH), which is associated with the development of inflammation, fibrosis, liver cancer and liver failure. The present study describes a human adipose-liver-on-a-chip model that enables the modelling and research of NAFLD under different metabolic conditions. By integrating human liver and fat cells into a recirculating, serum-free circulatory medium (two-chamber model), the researchers were able to study the metabolic interactions between the tissues over a period of 14 days. In order to evaluate the interactions between liver and fat cells and their significance for a pathological course, monocultures were analyzed in parallel. Different metabolic conditions (healthy, diabetic, obese and pro-inflammatory with TNF-alpha) were simulated in the model via variation of the circulatory medium. In addition, treatment with the antidiabetic drug metformin was evaluated. The results showed that the liver cells are indirectly damaged by insulin-resistant biomarkers and signalling substances of the fat cells, which are characteristic of pathologically progressive NAFDL. The signal cascades and tissue damage differed depending on the medium and model used. In contrast to monocultures, TNF-α-induced steatosis could also be detected in the two-chamber model. Treatment with metformin was able to reduce NASH at doses above the physiological range in isolated liver cells, but in parallel, it led to increased cytotoxicity and cell death. Based on the results, the adipose-liver-on-chip model shows promise for further investigation of aspects of the contribution of a single factor to NAFLD development, as well as for evaluating the preclinical efficacy of drugs and re-evaluating dosage regimens in humans.
Validation of an adipose-liver human-on-a-chip model of NAFLD for preclinical therapeutic efficacy evaluation
James J. Hickman
Added on: 09-07-2022
[1] https://www.nature.com/articles/s41598-021-92264-2
