Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis
Nature Biotechnology, vol. 41, pp. 1567–1581
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 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.
Authors 12
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Delilah F. G. Hendriks corresponding
Royal Netherlands Academy of Arts and Sciences · Oncode Institute · Hubrecht Institute for Developmental Biology and Stem Cell Research
Affiliation as printed
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands. d.hendriks@hubrecht.eu
Oncode Institute, Utrecht, The Netherlands. d.hendriks@hubrecht.eu
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands
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Avans University of Applied Sciences · Utrecht University · University Medical Center Utrecht
Affiliation as printed
Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
Research Group Analysis Techniques in the Life Sciences, School of Life Sciences and Technology, Avans University of Applied Sciences, Breda, The Netherlands
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Royal Netherlands Academy of Arts and Sciences · Oncode Institute
Affiliation as printed
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands
Oncode Institute, Utrecht, The Netherlands
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Royal Netherlands Academy of Arts and Sciences · Oncode Institute
Affiliation as printed
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands
Oncode Institute, Utrecht, The Netherlands
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Royal Netherlands Academy of Arts and Sciences · Oncode Institute
Affiliation as printed
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands
Oncode Institute, Utrecht, The Netherlands
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Affiliation as printed
The Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
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Affiliation as printed
The Maastricht Multimodal Molecular Imaging Institute, Maastricht University, Maastricht, The Netherlands
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Affiliation as printed
The Maastricht Multimodal Molecular Imaging Institute, Maastricht University, Maastricht, The Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands
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Benedetta Artegiani corresponding
Royal Netherlands Academy of Arts and Sciences · Princess Máxima Center
Affiliation as printed
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands. b.a.artegiani@prinsesmaximacentrum.nl
The Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands. b.a.artegiani@prinsesmaximacentrum.nl
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands
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Hans C. Clevers corresponding
Roche (Switzerland) · Royal Netherlands Academy of Arts and Sciences · University Medical Center Utrecht · Oncode Institute · Hubrecht Institute for Developmental Biology and Stem Cell Research · Princess Máxima Center
Affiliation as printed
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands. h.clevers@hubrecht.eu
Oncode Institute, Utrecht, The Netherlands. h.clevers@hubrecht.eu
Pharma, Research and Early Development of F. Hoffmann-La Roche Ltd, Basel, Switzerland. h.clevers@hubrecht.eu
The Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands. h.clevers@hubrecht.eu
University Medical Center Utrecht, Utrecht, The Netherlands. h.clevers@hubrecht.eu
Oncode Institute, Utrecht, The Netherlands
Cited by 248 stored of 248
Cited by patents worldwide 1 (Lens.org)
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Non-alcoholic fatty liver organ model and preparation method and application thereofCN118909928A 2024-11-08 Discontinued