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Modelling non-alcoholic fatty liver disease in human hepatocyte-like cells.

TitleModelling non-alcoholic fatty liver disease in human hepatocyte-like cells.
Publication TypeJournal Article
Year of Publication2018
AuthorsLyall MJ, Cartier J, Thomson JP, Cameron K, Meseguer-Ripolles J, O'Duibhir E, Szkolnicka D, Villarin BLucendo, Wang Y, Blanco GRodriguez, Dunn WB, Meehan RR, Hay DC, Drake AJ
JournalPhilos Trans R Soc Lond B Biol Sci
Volume373
Issue1750
Date Published2018 Jul 05
ISSN1471-2970
Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in developed countries. An NAFLD model would permit mechanistic studies and enable high-throughput therapeutic screening. While hepatic cancer-derived cell lines are a convenient, renewable resource, their genomic, epigenomic and functional alterations mean their utility in NAFLD modelling is unclear. Additionally, the epigenetic mark 5-hydroxymethylcytosine (5hmC), a cell lineage identifier, is rapidly lost during cell culture, alongside expression of the Ten-eleven-translocation () methylcytosine dioxygenase enzymes, restricting meaningful epigenetic analysis. Hepatocyte-like cells (HLCs) derived from human embryonic stem cells can provide a non-neoplastic, renewable model for liver research. Here, we have developed a model of NAFLD using HLCs exposed to lactate, pyruvate and octanoic acid (LPO) that bear all the hallmarks, including 5hmC profiles, of liver functionality. We exposed HLCs to LPO for 48 h to induce lipid accumulation. We characterized the transcriptome using RNA-seq, the metabolome using ultra-performance liquid chromatography-mass spectrometry and the epigenome using 5-hydroxymethylation DNA immunoprecipitation (hmeDIP) sequencing. LPO exposure induced an NAFLD phenotype in HLCs with transcriptional and metabolomic dysregulation consistent with those present in human NAFLD. HLCs maintain expression of the enzymes and have a liver-like epigenome. LPO exposure-induced 5hmC enrichment at lipid synthesis and transport genes. HLCs treated with LPO recapitulate the transcriptional and metabolic dysregulation seen in NAFLD and additionally retain expression and 5hmC. This model of NAFLD will be useful for future mechanistic and therapeutic studies.This article is part of the theme issue 'Designer human tissue: coming to a lab near you'.

DOI10.1098/rstb.2017.0362
Alternate JournalPhilos. Trans. R. Soc. Lond., B, Biol. Sci.
PubMed ID29786565
PubMed Central IDPMC5974453
Grant List / / Wellcome Trust / United Kingdom
MC_PC_U127574433 / / Medical Research Council / United Kingdom
MR/K026666/1 / / Medical Research Council / United Kingdom
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