Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis
Royal Netherlands Academy of Arts and Sciences · Oncode Institute · +7 more institutions
Abstract
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…
Citation impact
- FWCI
- 45.70
- Percentile
- 100%
- References
- 74
Authors
12- DHDelilah HendriksCorresponding
Royal Netherlands Academy of Arts and Sciences, Oncode Institute, Hubrecht Institute for Developmental Biology and Stem Cell Research
- JFJos F. Brouwers
Avans University of Applied Sciences, University Medical Center Utrecht
- KMKarien M. Hamer
Royal Netherlands Academy of Arts and Sciences, Oncode Institute
- MHMaarten H. Geurts
Royal Netherlands Academy of Arts and Sciences, Oncode Institute
- LLLéa Luciana
Royal Netherlands Academy of Arts and Sciences, Oncode Institute
Topics & keywords
- Steatosis
- Lipogenesis
- Fatty liver
- Biology
- Drug discovery
- Nonalcoholic fatty liver disease
- Lipid metabolism
- Bioinformatics
- Good health and well-being