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

Sinton, M. et al. (2021) A human pluripotent stem cell model for the analysis of metabolic dysfunction in hepatic steatosis. iScience, 24(1), 101931. (doi: 10.1016/j.isci.2020.101931) (PMID:33409477) (PMCID:PMC7773967)

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. C 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sinton, Dr Matthew
• Authors: Sinton, M., Meseguer-Ripolles, J., Lucendo-Villarin, B., Wernig-Zorc, S., Thomson, J. P., Carter, R. N., Lyall, M. J., Walker, P. D., Thakker, A., Meehan, R. R., Lavery, G. G., Morton, N. M., Ludwig, C., Tennant, D. A., Hay, D. C., and Drake, A. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: iScience
• Publisher: Cell Press
• ISSN: 2589-0042
• ISSN (Online): 2589-0042
• Published Online: 01 December 2020
• Copyright Holders: Copyright © 2020 The Author(s)
• First Published: First published in iScience 24(1):101931
• Publisher Policy: Reproduced under a Creative Commons license