摘要：SummaryNonalcoholic 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.Graphical AbstractDisplay OmittedHighlights•LPO-exposed hPSC-derived hepatocyte-like cells resemble human hepatic steatosis•Steatosis is associated with decreased mitochondrial maximal respiration•Purine nucleotide cycle activity increases in steatotic hepatocytes•Excess fumarate production is associated with induction of macrovesicular steatosisEndocrine System Physiology; Stem Cells Research; Transcriptomics
