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.
Bibliographical noteFunding Information:
MCS was supported by a British Heart Foundation PhD studentship (FS/16/54/32730) and the British Heart Foundation Centre of Research Excellence . SW-Z was funded by the Deutsche Forschungsgemeinschaft ( SFB960 ). This work was supported in part by the Wellcome Trust [grant number 208400/Z/17/Z ], and we thank HWB-NMR at the University of Birmingham for providing open access to their Wellcome Trust-funded NMR equipment. RNC and NMM were supported by a Wellcome Trust New Investigator Award to NMM (100981/Z/13/Z). MJL was supported by a Wellcome Trust PhD Fellowship as part of the Edinburgh Clinical Academic Track scheme (102839/Z/13/Z). RRM is supported by the Medical Research Council and by grants from the BBSRC . Research in RRM's lab leading to these results is partly funded by the Innovative Medicine Initiative Joint Undertaking (IMI JU) under grant agreement number 115001 (MARCAR project: URL: http://www.imi-marcar.eu/ ) . DCH, JMR, and BLV were supported with awards from the MRC Doctoral Training Partnership (MR/K501293/1) and the Chief Scientist Office (TCS/16/37). AJD was funded by the British Heart Foundation Centre of Research Excellence , University of Edinburgh . Our thanks go to the Wellcome Trust Clinical Research Facility Genetics Core, Western General Hospital, Edinburgh, UK. We thank Will Cawthorn for discussions about mitochondrial quantification. Graphical abstract and Figure 1 A were created using the BioRender platform.
- Endocrine System Physiology
- Stem Cells Research
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