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

Delilah Hendriks, Jos F Brouwers, Karien Hamer, Maarten H Geurts, Léa Luciana, Simone Massalini, Carmen López-Iglesias, Peter J Peters, Maria J Rodríguez-Colman, Susana Chuva de Sousa Lopes, Benedetta Artegiani, Hans Clevers

Research output: Contribution to journal/periodicalArticleScientificpeer-review

44 Citations (Scopus)

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-/- organoids. From a screen targeting 35 genes implicated in lipid metabolism and/or NAFLD risk, FADS2 (fatty acid desaturase 2) emerged as an important determinant of hepatic steatosis. Enhancement of FADS2 expression increases polyunsaturated fatty acid abundancy which, in turn, reduces de novo lipogenesis. These organoid models facilitate study of steatosis etiology and drug targets.

Original languageEnglish
Pages (from-to)1567-1581
Number of pages15
JournalNature Biotechnology
Volume41
Issue number11
DOIs
Publication statusPublished - Nov 2023

Keywords

  • Humans
  • Non-alcoholic Fatty Liver Disease/drug therapy
  • Drug Evaluation, Preclinical
  • Hepatocytes/metabolism
  • Lipid Metabolism
  • Apolipoproteins B/metabolism
  • Liver/metabolism

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