Human liver organoid: modeling liver steatosis and beyond

Abstract Steatosis, as the early stage of nonalcoholic fatty acid disease (NAFLD), would progress into nonalcoholic steatohepatitis (NASH) and liver failure without intervention. Despite the development of animal models, there is still a lack of the human-relevant platform for steatosis modeling and drug & target discovery. Hendriks et al., reporting in Nature Biotechnology, leveraged human fetal liver organoids to recapitulate steatosis by introducing nutritional and genetic triggers. Using these engineered liver organoid-derived steatosis models, they screened drugs that alleviate steatosis, and mined common mechanism of effective compounds. Further, inspired by the results of drug screening, the arrayed CRISPR-LOF screening targeting 35 lipid metabolism genes was performed, and FADS2 was identified as a critical regulator of steatosis.