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

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Article number101931
JournaliScience
Volume24
Issue number1
Early online date11 Dec 2020
DOIs
Publication statusPublished - 22 Jan 2021

Fingerprint Dive into the research topics of 'A human pluripotent stem cell model for the analysis of metabolic dysfunction in hepatic steatosis'. Together they form a unique fingerprint.

Cite this