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Article

Pluripotent Stem Cell-Derived Hepatocytes Phenotypic Screening Reveals Small Molecules Targeting the CDK2/4-C/EBPα/DGAT2 Pathway Preventing ER-Stress Induced Lipid Accumulation

1
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
2
Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
3
Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK
4
Molecular AI, Discovery Sciences, R&D, AstraZeneca, 431 83 Mölndal, Sweden
5
Emerging Innovations Unit, Discovery Sciences, R&D, AstraZeneca, Cambridge SG8 6HB, UK
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(24), 9557; https://doi.org/10.3390/ijms21249557
Received: 25 October 2020 / Revised: 17 November 2020 / Accepted: 26 November 2020 / Published: 15 December 2020
Non-alcoholic fatty liver disease (NAFLD) has a large impact on global health. At the onset of disease, NAFLD is characterized by hepatic steatosis defined by the accumulation of triglycerides stored as lipid droplets. Developing therapeutics against NAFLD and progression to non-alcoholic steatohepatitis (NASH) remains a high priority in the medical and scientific community. Drug discovery programs to identify potential therapeutic compounds have supported high throughput/high-content screening of in vitro human-relevant models of NAFLD to accelerate development of efficacious anti-steatotic medicines. Human induced pluripotent stem cell (hiPSC) technology is a powerful platform for disease modeling and therapeutic assessment for cell-based therapy and personalized medicine. In this study, we applied AstraZeneca’s chemogenomic library, hiPSC technology and multiplexed high content screening to identify compounds that significantly reduced intracellular neutral lipid content. Among 13,000 compounds screened, we identified hits that protect against hiPSC-derived hepatic endoplasmic reticulum stress-induced steatosis by a mechanism of action including inhibition of the cyclin D3-cyclin-dependent kinase 2-4 (CDK2-4)/CCAAT-enhancer-binding proteins (C/EBPα)/diacylglycerol acyltransferase 2 (DGAT2) pathway, followed by alteration of the expression of downstream genes related to NAFLD. These findings demonstrate that our phenotypic platform provides a reliable approach in drug discovery, to identify novel drugs for treatment of fatty liver disease as well as to elucidate their underlying mechanisms. View Full-Text
Keywords: human induced pluripotent stem cell-derived hepatocytes; chemogenomic library screening; quantitative high-content microscopy analysis; lipid droplets; steatosis; NAFLD; drug discovery; open innovation; CDK4-C/EBPα/DGAT2 pathway human induced pluripotent stem cell-derived hepatocytes; chemogenomic library screening; quantitative high-content microscopy analysis; lipid droplets; steatosis; NAFLD; drug discovery; open innovation; CDK4-C/EBPα/DGAT2 pathway
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MDPI and ACS Style

Parafati, M.; Bae, S.H.; Kirby, R.J.; Fitzek, M.; Iyer, P.; Engkvist, O.; Smith, D.M.; Malany, S. Pluripotent Stem Cell-Derived Hepatocytes Phenotypic Screening Reveals Small Molecules Targeting the CDK2/4-C/EBPα/DGAT2 Pathway Preventing ER-Stress Induced Lipid Accumulation. Int. J. Mol. Sci. 2020, 21, 9557. https://doi.org/10.3390/ijms21249557

AMA Style

Parafati M, Bae SH, Kirby RJ, Fitzek M, Iyer P, Engkvist O, Smith DM, Malany S. Pluripotent Stem Cell-Derived Hepatocytes Phenotypic Screening Reveals Small Molecules Targeting the CDK2/4-C/EBPα/DGAT2 Pathway Preventing ER-Stress Induced Lipid Accumulation. International Journal of Molecular Sciences. 2020; 21(24):9557. https://doi.org/10.3390/ijms21249557

Chicago/Turabian Style

Parafati, Maddalena, Sang Hyo Bae, R. Jason Kirby, Martina Fitzek, Preeti Iyer, Ola Engkvist, David M. Smith, and Siobhan Malany. 2020. "Pluripotent Stem Cell-Derived Hepatocytes Phenotypic Screening Reveals Small Molecules Targeting the CDK2/4-C/EBPα/DGAT2 Pathway Preventing ER-Stress Induced Lipid Accumulation" International Journal of Molecular Sciences 21, no. 24: 9557. https://doi.org/10.3390/ijms21249557

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