Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis.

ABSTRACT: The lack of registered drugs for nonalcoholic fatty liver disease (NAFLD) is partly due to the paucity of human-relevant models for target discovery and compound screening. Here we use human fetal hepatocyte organoids to model the first stage of NAFLD, steatosis, representing three different triggers: free fatty acid loading, interindividual genetic variability (PNPLA3 I148M) and monogenic lipid disorders (APOB and MTTP mutations). Screening of drug candidates revealed compounds effective at resolving steatosis. Mechanistic evaluation of effective drugs uncovered repression of de novo lipogenesis as the convergent molecular pathway. We present FatTracer, a CRISPR screening platform to identify steatosis modulators and putative targets using APOB^-/- and MTTP^-/- organoi

SUBMITTER: Hendriks D 

PROVIDER: S-EPMC10635827 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature