Mitochondrial toxicity in drug-induced fatty liver disease. Generalization of the causal relationship for the development of new predictive tests – MITOXDRUGS

Polymedication in our modern societies leads to an increased risk of drug-induced adverse effects including liver injury. Among drug-induced liver injury (DILI), steatosis (also known as fatty liver) is a major concern because of its relatively high frequency in treated patients and its potential progression to chronic liver diseases such as steatohepatitis and cirrhosis. Some studies previously suggested that a major mechanism whereby drugs could induce lipid accretion in the liver could be an impairment of the mitochondrial fatty acid oxidation (mtFAO). However, mtFAO impairment was investigated only for a few steatogenic drugs (e.g. amiodarone, tamoxifen, valproate) and a correlation between mtFAO alteration and steatosis was never generalized. Hence, the aim of our MITOXDRUGS project is to determine the effects of 30 steatogenic and 15 non-steatogenic drugs on mtFAO by using 3 different experimental models: 1) isolated mouse liver mitochondria, 2) the differentiated human hepatoma HepaRG cell line, and 3) larvae of zebrafish (Danio rerio). Different substrates of the mtFAO will be used in these models in order to clarify the mechanism(s) whereby these drugs can inhibit this major metabolic pathway. Mitochondrial reactive oxygen species will be measured in these different experimental models. Lipid accumulation will also be assessed in HepaRG cells and zebrafish larvae liver. Notably, the protocols of drug treatment will be identical for HepaRG cells and zebrafish larvae allowing meaningful comparison of the investigations performed in these two experimental models. This will be an important information in order to determine whether zebrafish larvae can be used as a simple and reliable model in order to predict drug-induced hepatic mtFAO impairment and steatosis. This project will involve Mitologics, a biotech specialized in the detection of mitochondrial alterations, two INSERM partners with a strong expertise in the study of DILI and/or mitochondrial function and one INSERM partner with a solid expertise in the use of zebrafish model. This project is expected to generate novel concepts in the field of drug-induced liver lesions, which can be serious and lead to the death of some patients. In addition, this project could allow Mitologics to propose to its clients (e.g. pharmaceutical and cosmetic industries) innovative tests in order to better predict iatrogenic mtFAO impairment and liver steatosis and thus, to preserve the well-being of treated patients.