A human pluripotent stem cell model for the analysis of metabolic dysfunction in hepatic steatosis

Matthew C Sinton; Jose Meseguer-Ripolles; Baltasar Lucendo-Villarin; Sara Wernig-Zorc; John P Thomson; Roderick N Carter; Marcus J Lyall; Paul D Walker; Alpesh Thakker; Richard R Meehan; Gareth G Lavery; Nicholas M Morton; Christian Ludwig; Daniel A Tennant; David C Hay; Amanda J Drake

doi:10.1016/j.isci.2020.101931

A human pluripotent stem cell model for the analysis of metabolic dysfunction in hepatic steatosis

iScience. 2020 Dec 11;24(1):101931. doi: 10.1016/j.isci.2020.101931. eCollection 2021 Jan 22.

Authors

Matthew C Sinton¹, Jose Meseguer-Ripolles², Baltasar Lucendo-Villarin², Sara Wernig-Zorc³, John P Thomson⁴, Roderick N Carter¹, Marcus J Lyall¹, Paul D Walker⁵, Alpesh Thakker⁵, Richard R Meehan⁴, Gareth G Lavery⁵, Nicholas M Morton¹, Christian Ludwig⁵, Daniel A Tennant⁵, David C Hay², Amanda J Drake¹

Affiliations

¹ University/BHF Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh BioQuarter, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
² Centre for Regenerative Medicine, University of Edinburgh, Institute for Regeneration and Repair, Edinburgh BioQuarter, 5 Little France Crescent, Edinburgh, EH16 4UU, UK.
³ Department of Biochemistry, University of Regensburg, Universitätsstraße 31, 93053 Regensburg, Germany.
⁴ Human Genetics Unit, University of Edinburgh, MRC Institute for Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4, 2XU, UK.
⁵ Institute of Metabolism and Systems Research, IBR Tower, College of Medical and Dental Sciences, Edgbaston, University of Birmingham, Birmingham, B15 2TT,, UK.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is currently the most prevalent form of liver disease worldwide. This term encompasses a spectrum of pathologies, from benign hepatic steatosis to non-alcoholic steatohepatitis, which have, to date, been challenging to model in the laboratory setting. Here, we present a human pluripotent stem cell (hPSC)-derived model of hepatic steatosis, which overcomes inherent challenges of current models and provides insights into the metabolic rewiring associated with steatosis. Following induction of macrovesicular steatosis in hepatocyte-like cells using lactate, pyruvate, and octanoate (LPO), respirometry and transcriptomic analyses revealed compromised electron transport chain activity. ¹³C isotopic tracing studies revealed enhanced TCA cycle anaplerosis, with concomitant development of a compensatory purine nucleotide cycle shunt leading to excess generation of fumarate. This model of hepatic steatosis is reproducible, scalable, and overcomes the challenges of studying mitochondrial metabolism in currently available models.

Keywords: Endocrine System Physiology; Stem Cells Research; Transcriptomics.

Abstract

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